Stearn began his career as a gardener at Sidney Sussex College after leaving school at 13. He then became a bookseller at Bowes & Bowes. While working at the bookshop he made many friends among the Cambridge botanists and participated in their activities, including botanical excursions. In addition to Professor Seward, those influencing him included the morphologist Agnes Arber, Humphrey Gilbert-Carter the first scientific director of the Botanic Garden, John Gilmour then curator of the university herbarium and later director of the Garden (1951–1973), the horticulturalist E. A. Bowles (1865–1954), who became his patron, Harry Godwin, then a research fellow and later professor and Tom Tutin who was working with Seward at that time. Seward gave him full research facilities in the herbarium. He continued his research, visiting the Royal Botanical Gardens, Kew, in 1930, at the age of 19, and also spent two weeks at the herbarium of the Musée National d'Histoire Naturelle, Paris, with the aid of a £15 grant from the Royal Society to study Epimedium. Also in 1930, the Fifth International Botanical Congress was held at Cambridge, and Stearn was able to attend. During this time he commuted between the bookshop, the Botany School, Botanic Garden and home by bicycle, his preferred means of transportation throughout his life.

In 1933, H. R. Hutchinson, who was the Librarian at the Lindley Library, Royal Horticultural Society's (RHS) in London, was due to retire. John Gilmour, now assistant director at the Kew Gardens, put forward Stearn's name, together with Bowles, a vice-president of the Society, who had discovered Stearn at the bookshop. Stearn was 22 when he began work at the library, initially as assistant librarian, before taking over Hutchinson's position after six months. He later explained his appointment at such a young age as being the result of World War I: "All the people who should have had those jobs were dead." There he collaborated with Bowles on a number of plant monographs, such as Bowles' Handbook of Crocus and their work on Anemone japonica (Anemone hupehensis var. japonica). Written in 1947, it is still considered one of the most comprehensive accounts of the origins and nomenclature of autumn-blooming anemones. Stearn was one of the last people to see Bowles alive, and when Bowles died, Stearn wrote an appreciation of him, and later contributed the entry on Bowles to the Oxford Dictionary of National Biography. Much of his spare time was spent studying at the Kew Gardens.

The Lindley Library, the largest horticultural library in the world and named after the British botanist John Lindley (1799–1865), was established in 1868 by the acquisition of Lindley's 1,300 volumes upon his death. It had recently undergone considerable change. In 1930, the library had been rehoused in a new floor added to the society's Vincent Square headquarters, but the role of the library was somewhat downgraded. Frederick Chittenden had been appointed as Keeper of the Library (1930–1939), and Hutchinson reported directly to him. Stearn related that when he reported for duty, Hutchinson was completely unaware of the appointment of his new assistant.

Lindley was one of Stearn's inspirations, also being a librarian who had a long association with the RHS. Lindley also bequeathed his herbarium to the Cambridge University Herbarium, where it now forms the Lindley Collection. As Stearn remarked "I came to know his numerous publications and to admire the industry, tenacity and ability with which he undertook successfully so many different things". Later Stearn would publish a major work on Lindley's life and work. Lindley's contributions to horticultural taxonomy were matched only by those of Stearn himself. Stearn soon set about using his antiquarian knowledge to reorganise the library, forming a pre-Linnean section. Not long after his arrival the library acquired one of its largest collections, the Reginald Cory Bequest (1934), which Stearn set about cataloguing on its arrival two years later, resulting in at least fifteen publications.

While at the library he continued his self-education through evening classes, learning Swedish, and travelling widely. Stearn used his three-week annual leaves in the pre-war years to visit other European botanical libraries, botanic gardens, museums, herbaria and collections, as well as collecting plants, with special emphasis on Epimedium and Allium. His travels took him to Switzerland, Italy, Germany, Austria, Czechoslovakia, Denmark, and Sweden.

The only break from this employment was the war years 1941–1946, leaving his assistant Miss Cardew as acting librarian. Initially Stearn served as an air raid warden, before enlisting. As a conscientious objector, he could not serve in a combatant role, but was accepted into the Royal Air Force (RAF) Medical Services, as he had previously worked with the St John Ambulance Brigade. He served in the RAF in both England, and Asia (India and Burma, where he worked in intelligence, and was awarded the Burma Star). While there he undertook studies of Indo-Malayan and Sikkim-Himalayan tropical vegetation, carried out botanical explorations, taught biology to troops and began work on his Botanical Latin. His wartime observations led to collaborative publications such as An enumeration of the flowering plants of Nepal (1978–1982), Beautiful Indian Trees (2nd ed. 1954), as well as works on Himalayan species of Allium. On returning from the war, Stearn and his new wife, Eldwyth Ruth Stearn, were obliged to live in the Lindley Library for a while till they found a more permanent home, due to the acute housing shortage in London.

From the Lindley Library, Stearn (see 1950 Photograph) moved to the Botany Department at the Natural History Museum, South Kensington in 1952, and by the time he retired in 1976, he was the Senior Principal Scientific Officer there. He had now achieved his aim of becoming a research scientist, despite lack of formal qualifications, enabling him to spend more of his time collecting and studying plants. During this time the museum was undergoing steady expansion, with new staff and programmes. At the museum he was put in charge of Section 3 of the General Herbarium (the last third of the Dicotyledons in the Bentham & Hooker system, i.e., Monochlamydae) and floristic treatment of the regions of Europe, Jamaica, the United States, Australia and Nepal, including work on the museum's Flora of Jamaica and the Nepal flora he started work on during the war. Seven volumes of the Flora of Jamaica had appeared prior to the Second World War. Although the project was revived after the war, and Stearn carried out six months of field work in Jamaica, it never came to fruition; no further volumes appeared. In Jamaica, Stearn followed in the footsteps of Sir Hans Sloane (1660–1753), whose collection had been left to the Natural History Museum. Stearn's generic work at the museum concentrated on Allium, Lilium and Paeonia. He continued to travel widely, with field work in Europe (particularly Greece), Australia, and the United States, and published 200 papers during his 24 years at the museum, and although the library was not his responsibility, he spent much time there adding written notes to many of the critical texts.

While at the museum, Stearn became increasingly involved in the work of the Linnean Society during his Kensington years. He was also offered the George A. Miller professorship of botany at the University of Illinois (1966), but felt he would be unable to leave his commitments in London. At the time of his retirement in 1976, he was still using a fountain pen as his only means of communication and scholarship, a fact commemorated by his retirement present of a Mont Blanc pen capable of writing for long periods without refills.

Following his retirement on 30 November 1976, he continued to work, both at the museum and at the Royal Botanical Gardens, Kew, where his home at 17 High Park Road, Kew Gardens, Richmond (see image), gave him access to the herbarium and library, a short bicycle trip away. Indeed, 35% of his total publications appeared in the quarter century of his retirement. He was commissioned to write a history of the museum for its centenary (1981), although he did so with some difficulty, due to deadlines and budget constraints. The task, which took three years, was made more difficult for him by the museum's decision to censor his critical comments. He continued his association with the Lindley Library all his life, being an active committee member and regularly attended RHS flower shows even after he was barely able to walk.

As a student of the classics he was passionate about Greece, its mountains and plants (such as Paeonia) and all things Greek, both ancient and modern. The Stearns had formed a friendship with Constantine Goulimis and Niki and Angelos Goulandris, founders of the Goulandris Museum of Natural History in Kifissia, Athens. Stearn first met the Goulandris' in 1967 and offered practical help with their museum. He also stayed with them when he and his wife visited Greece. Niki Goulandris illustrated both Wild Flowers of Greece that Goulimis and Stearn wrote in 1968, as well as his Peonies of Greece (1984). The latter work typified Stearn's encyclopedic approach, including topics such as mythology and herbalism in addition to taxonomy. Stearn then took on the editorship of Annales Musei Goulandris, the scientific journal of the museum (1976–1999), succeeding Werner Greuter, the first editor, having been instrumental in getting the journal launched in 1973. Eldwyth Ruth Stearn took on the job of compiling the indexes. When he retired from this position he was 88, and was succeeded by John Akeroyd. He was a liberal contributor to the journal, and during this time he and Eldwyth Ruth Stearn undertook their translation of The Greek Plant World in Myth, Art, and Literature (1993).

Stearn was a member of the Linnean Society for many years, becoming a fellow as early as 1934. He served as botanical curator 1959–1985, council member 1959–1963 and as vice-president 1961–1962 and president 1979–1982, producing a revised and updated history of the society in 1988. He also served as president of the Garden History Society and the Ray Society (1975–1977). The Royal Horticultural Society had made him an honorary fellow in 1946 and in 1986 he became a vice-president. Stearn became a member of the Botanical Society of Britain and Ireland (BSBI) in 1954, joining the Maps Committee the following year to prepare their Atlas of the British Flora (1962). He remained on that committee till 1968, when it became the Records Committee. For 40 years he was the BSBI referee for Allium. While at the Lindley Library, he became a founding member of the Society for the Bibliography of Natural History (later, the Society for the History of Natural History) in 1936, was one of its most active publishing members based on his cataloguing work at the library, and published a history of the society for their 50th anniversary in 1986. Other societies on which he served include the British Society for the History of Science (vice-president), the British Society for the History of Medicine (Council), the Garden History Society (president 1977–1982) and was a corresponding member of the Botanical Society of America.

Stearn was appointed Sandars Reader in Bibliography, University of Cambridge in 1965 speaking on "Bibliography in the Service of Biology."

From 1977 to 1983 he was visiting professor at Cambridge University's Department of Botany, and also visiting professor in botany at Reading University 1977–1983, and then Honorary Research Fellow (1983–). He was also a fellow of the Institute of Biology (1967) and was elected an Honorary Fellow of Sidney Sussex College, Cambridge in 1968.

William Stearn was the author of nearly 500 publications, including his autobiography. These included monographs, partial floras, books on botanical illustration, scholarly editions of historical botanical texts, dictionaries, bibliographies and botanical histories.

During Stearn's initial four years in Cambridge (1929–1933), he published twenty-four papers, predominantly in the Gardeners' Chronicle and Gardening Illustrated and the Journal of Botany, his first in 1929. While working as a gardener's boy during school holidays he had observed a specimen of Campanula pusilla (Campanula cochleariifolia) with a distorted corolla. He then described and published the first appearance of the causative agent, the mould Peronospora corollaea, in Britain, using the facilities of the Botany library.

At the Botanic Garden he developed a special interest in Vinca, Epimedium, Hosta and Symphytum, all of which he published monographs on. A series of botanical publications followed, starting with a new species of Allium (A. farreri Stearn, 1930). Stearn repeatedly returned to the genus Allium, and was considered a world expert on it; many species bear his name. 1930 would also see his first bibliographic work, on the botanist Reginald Farrer, whom he named Allium farreri after, and also described Rosa farreri (1933) and other species named after Farrer. It was while he was compiling Farrer's works in 1930 that he came across the latter's work, The English Rock-Garden (1919) and its account of Barren-worts (Epimedium), and kindled a lifetime interest in the genus. From 1932, he produced a series of papers on this genus, studying it at Cambridge, Kew and Paris. It became one of the genera which he was best known, and many species of which now bear his name. Epimedium and the related woodland perennial Vancouveria (Berberidaceae) would be the subject of his first monograph (1938) and were genera to which he would return at the end of his life. At the time the taxonomy of this genus was very confused, and with the help of the Cambridge Herbarium he obtained specimens from all over Europe to produce a comprehensive monograph. The work was so thorough that it was mistakenly considered a doctoral thesis by other botanists. He also began a series of contributions to the catalogue of the Herbarium, together with Gilmour and Tutin. With John Gilmour he issued two exsiccata-like works Herbarium florae Cantabrigiensis and Sertum Cantabrigiense exsiccatum (1933).

After moving to London, Stearn produced a steady output of publications during his years at the Royal Horticultural Society's Lindley Library (1933–1952). These covered a wide range of topics from bibliography to plant nomenclature, taxonomy and garden plants, with a particular emphasis on Vinca, Epimedium and Lilium. Within two years of joining the library in 1933, he had produced his first major monograph, Lilies (1935), in collaboration with Drysdale Woodcock and John Coutts. This text, in an expanded and revised edition, as Woodcock and Stearn's Lilies of the World (1950) became a standard work on the Liliaceae sensu lato. While at the library he also continued his collaboration with his Cambridge colleagues, publishing catalogues of the Herbarium collections, including the Catalogue of the Collections of the Herbarium of the University Botany School, Cambridge (1935). The second task imposed on him at this time involved the RHS role in maintaining revision of the International Code of Botanical Nomenclature (see Botanical taxonomy).

After his return to London in 1946, at the end of the Second World War, a number of major publications ensued, including Lilies of the World in 1950. The RHS also imposed two major tasks on their librarian. In 1950, Frederick Chittenden, a previous director of RHS Wisley and Keeper of the Library, died leaving unfinished the four volume RHS Dictionary of Gardening that the society had commissioned from him before the war. The war had interrupted the work as many of the expected contributors were unavailable. Stearn, together with Patrick Synge, the RHS Publications Editor, undertook to complete the work, particularly volume IV (R–Z), a task he completed within six months, with 50 new articles. The finished work was published in 1951 and not only did he undertake the role of editing this large work but his contributions covered 50 genera, 600 species and complex identification keys such as Solidago and Viola. Since Stearn's entries in volume IV extended from Soldanella to Zygotritonia, he would jest that he was but "a peculiar authority on plants from 'So-' onwards". He issued a revised version in 1956 with Synge in which he added a further 86 articles. His recollection of this task was that he acquired "that occupational hazard of compilers of encyclopaedias", encyclopedic knowledge.

Many of Stearn's collaborative works used his bibliographic skills. While his genus monographs largely concentrated on Mediterranean flora, notably Epimedium, Allium and Paeonia, he was also the author of species articles both popular and technical as well as a number of classical treatises. In addition he produced floristic treatments of a number of regions such as Jamaica and Nepal. He also contributed to many national Florae as diverse as Bhutan and Greece, as well as major regional florae including the Flora Europaea and European Garden Flora.

While his output covered a wide range of topics, he is best known for his contributions to botanical history, taxonomy, botanical bibliography, and botanical illustration. Botanical Latin (four editions 1966–1992), is his best known work, having become a standard reference and described as both the bible of plant taxonomists and a philological masterwork. It was begun during the war years and the first edition was basically a guide to Latin for botanists with no or limited knowledge of the language, which he described as a "do-it-yourself Latin kit" for taxonomists. Later, the work evolved into an etymological dictionary, but then Stearn learned that such a work had already been published in the Netherlands before the war. He then continued to expand it with the assistance of his wife and son, systematically collecting botanical terms from botanical texts. It is said that only he could have written this work, which explains not just the derivation of plant names but also the philological principles involved in forming those names. The work is considered responsible for the continued survival of Latin as the lingua franca of botany. In addition to this seminal text, he frequently delighted in the illumination that the classics could add to understanding plants and plant lore, such as his Five Brethren of the Rose (1965).

His best known popular work is his Dictionary of Plant Names, which found its way into the libraries of most horticulturalists. One of the focuses of his work at the Natural History Museum was the flora of the Caribbean, where he carried out field work. Stearn continued to return to the Cambridge Botanic Garden, cared for his own garden and worked with the RHS to become an authority on horticulture as well as botany. William Stearn collaborated with his wife, Eldwyth Ruth Stearn, on a number of his most important works, including Botanical Latin and Dictionary of Plant Names and translating German botanical history into English. Just before his death he completed a revision of his original Epimedium monograph.

William Stearn wrote extensively on the history of botany and horticulture, from Ancient Greece to his own times. He collected together J. E. Raven's 1976 J. H. Gray Lectures, editing and annotating them as Plants and Plant Lore in Ancient Greece (1990). In 1993, he and Eldwyth Ruth Stearn translated and expanded Baumann's Die griechische Pflanzenwelt in Mythos, Kunst und Literatur (1986) as The Greek Plant World in Myth, Art, and Literature.

Stearn compiled a major work on the life of John Lindley and produced an edited version of the classic book on herbals by Agnes Arber, one of the influences of his Cambridge years, and whose obituary he would later write for The Times. He also wrote a number of histories of the organisations he worked with as well as a number of introductions and commentaries on classic botanical texts such as John Ray's Synopsis methodica stirpium Britannicarum (1691), together with historical introductions to reference books, including Desmond's Dictionary of British and Irish Botanists (1994).

In his Botanical Gardens and Botanical Literature in the Eighteenth Century (1961), Stearn provides some insight into his interpretation of botanical history:

The progress of botany, as of other sciences, comes from the interaction of so many factors that undue emphasis on any one can give a very distorted impression of the whole, but certainly among the most important of these for any given period are the prevailing ideas and intellectual attitudes, the assumptions and stimuli of the time, for often upon them depends the extent to which a particular study attracts an unbroken succession of men of industry and originality intent on building a system of knowledge and communicating it successfully to others of like mind.

Stearn's historical research is best known for his work on Carl Linnaeus (1707–1778), which he began while at the Natural History Museum, and which won him a number of awards at home and abroad. Between 1953 and 1994 he produced more than 20 works describing Linnaeus' life and work.

Of Stearn's writings on Linnaeus, the most well known is his edition of the 1753 Species plantarum, published in facsimile by the Ray Society in 1957, for which he wrote both a 176-page introduction and an appendix. Concerned that Linnaeus' methods were imperfectly understood by his contemporaries, Stearn wrote that his introduction "provided concisely all the information about his Linnaeus' life, herbaria, publications, methodology etc. which a botanical taxonomist needs to know". The Times stated that no other botanist possessed the historical knowledge and linguistic skills to write, what is considered one of the classic studies of the Swedish naturalist and a highpoint of 20th century botanical scholarship. Subsequently, Stearn became a recognised authority on Linnaeus. Stearn produced similar introductions to a number of other editions of Linnaeus' works, including Genera Plantarum, Mantissa plantarum and Flora Anglica. Later, he would produce a bicentenary guide to Linnaeus (1978) for the Linnean Society.

Although Stearn spent much of his life studying and writing about Linnaeus, he did not admire the man's character, describing him as mean—"a jealous egoist, with a driving ambition". When asked which botanists in history he did admire, he cited John Lindley, Carolus Clusius (1526–1609) and Olof Swartz (1760–1818).

Stearn made major contributions to plant taxonomy and its history. In 1950 the Seventh International Botanical Congress was held in Stockholm, and the RHS would have been represented by Chittenden, but he had been taken ill. Bowles then arranged for Stearn and Gilmour to represent the society in his stead. The congress appointed a special committee to consider nomenclatural issues related to cultivated plants, which became known as the Committee for the Nomenclature of Cultivated Plants (the "Stockholm Committee"), with Stearn as secretary (1950–1953). Stearn then proposed an International Code of Nomenclature for Cultivated Plants (the "Cultivated Code"), producing the first draft that day. The code was accepted in principle by the committee, conditional on its approval by a parallel committee of the International Horticultural Congress (the Horticultural Nomenclature Committee), which would next meet in London in 1952 (the "London Committee"). Later that year Stearn was also appointed secretary of the London Committee so that he now represented both organisations. The two committees then met jointly on 22–24 November 1951 at the RHS building in London to draft a final joint proposal that was published by Stearn as secretary of an editorial committee and adopted by the 13th International Horticultural Congress the following year.

The resulting code was formulated as a supplement to the existing International Code of Botanical Nomenclature. Stearn introduced two important concepts, the terms "cultivar" and "grex". Cultivar, a term first proposed by L. H. Bailey in 1923, refers to a distinctive genus or species variety raised or maintained in cultivation, such as Euphorbia dulcis "Chameleon". Grex (Latin for "flock" or "herd") refers to a group of hybrids of common parentage, such as Lilium Pink Perfection Group. These concepts contributed a similar clarity to the nomenclature of garden or agricultural plants that Linnaeus had brought to the naming of native plants two centuries earlier. Stearn continued to play an active part in the International Botanical Congresses over many years, where he was remembered for his rhetorical persuasion on nomenclatural matters. He was also a pioneer in the application of computer-aided technology to (numerical taxonomy), as in his work on Columnea (1969).

Motivated by his interest in botanical history and taxonomy, Stearn devoted a considerable part of his output to botanical bibliography, including numerous papers and catalogues establishing the exact publication dates of books on natural history, particularly from the early nineteenth century, including William Herbert's work on Amaryllidaceae (1821, 1837) and complete bibliographies of botanists such as John Gilmour (1989). At the RHS library he transformed the minimalist card indexing by introducing British Museum rules and adding extensive bibliographic information. He quickly realised that one of the major deficits in contemporary taxonomic nomenclature was a lack of precise dates of all the names, and set about rectifying this over a fifteen-year period, resulting in 86 publications, which was a major step in stabilising nomenclature. The importance of this lay in the rules of botanical nomenclature, which gives botanical names priority based on dates of publication. He considered his most important contribution in this regard to be his elucidation of the dating of the early 19th century collection of studies of Canary Islands flora by Webb and Berthelot (1836–1850). Another important work from this period was on Ventenat's Jardin de la Malmaison (1803–1804), also published in the new Journal of the Society for the Bibliography of Natural History. In a number of instances his contributions to others' work went unacknowledged, particularly when he was younger, even though his introductions (often with the title "Revised and enlarged by W. T. Stearn") could be as lengthy as the texts they preceded. His contributions to botanical bibliography and in particular the correct interpretation of historical texts from Linnaeus to Arber are considered of central importance to the field of taxonomy.

Within a few years after Stearn returned from the war, his Art of Botanical Illustration (1950) was published, remaining the standard work on the subject to this day. There was, however, some bibliographic confusion – Collins, the publisher, had planned a book on botanical art for its New Naturalist series, but mistakenly commissioned both Stearn and the art historian Wilfred Blunt independently to produce the work. After the error was discovered the two decided to collaborate; Blunt wrote the work while Stearn edited and revised it. When it was published, Blunt's name was on the title page, while Stearn was only acknowledged in the preface. The omission was not rectified till he prepared the second edition in 1994, although the preface reveals Stearn's extensive contribution.

His continuing interest in botanical illustration led him to produce work on both historical and contemporary artists, including the Florilegium of Captain Cook and Joseph Banks from their first voyage (1768–1771) to the Pacific on the Endeavour, the similar account of Ferdinand Bauer's later botanical expedition to Australia with Matthew Flinders on the Investigator (1801–1803), and the work of illustrator Franz Bauer (the brother of Ferdinand). Stearn's studies of Ferdinand Bauer's Flora Graeca (1806–1840) enabled him to combine his passion for Greece with that of illustration. Other illustrators of this period that he wrote about included William Hooker.

William Stearn received three honorary doctorates during his lifetime, from Leiden (D.Sc. 1960), Cambridge (Sc.D. 1967), and Uppsala (Fil.Dr. 1972). He was the Masters Memorial Lecturer, Royal Horticultural Society in 1964. In 1976, the Linnean Society awarded him their Gold Medal for his contributions to Linnean scholarship and taxonomic botany. In 1985, he was the Wilkins Lecturer of the Royal Society, entitled Wilkins, John Ray, and Carl Linnaeus. In 1986, he received the Founder's Medal of the Society for the History of Natural History and in 1993, he received the Engler Gold Medal from the International Association for Plant Taxonomy. The Royal Horticultural Society awarded him both their Veitch Memorial Medal (1964) and Victoria Medal of Honour (VMH, 1965). In 2000, he received the Asa Gray Award, the highest honour of the American Society of Plant Taxonomists. Stearn was appointed a Commander of the Order of the British Empire (CBE) in the 1997 Birthday Honours for services to horticulture and botany.

He was well regarded in Sweden for his studies on Linnaeus, and possessed a good grasp of the language. In addition to his honorary doctorate from Uppsala, the Royal Swedish Academy of Sciences awarded him their Linnaeus Medal in 1972, he was granted the title of Commander of the Swedish Order of the Star of the North (Polar Star) in 1980 and admitted to membership of the Royal Swedish Academy of Sciences in 1983. Stearn was also elected to membership of the Swedish Linnaeus Society.