In 1850, in a wedding ceremony held in Newport, Kentucky, Bryan married Jennie "Jane" Byrd Page who became Mrs. Jennie Byrd Bryan. His wife was related, by marriage, to the prominent Page and Lee families of Virginia. She was the daughter of an episcopal clergyman.

In 1852, Bryan and his wife moved to Chicago, where he had acquired broad real estate interests. He was also involved in the construction of railroads. Over the next half-century, Bryan would be a booster in the growth of the city. Bryan also established a reputation for himself as a gifted orator.

Bryan and his wife Jennie had three children, two of whom (a son and a daughter) would live to adulthood. The son they lost as a child, Daniel Page Bryan, who died on April 12, 1855, at the age of five. Their adult son was Charles Page Bryan, born in 1855, who would have a career as a lawyer, politician, and diplomat. Their daughter, born in 1857, was also named Jennie Byrd Bryan. She would become an artist and philanthropist, and would, in 1913, marry John Barton Payne, adopting his surname.

Bryan's initial residence in Chicago was at 103 Michigan Avenue, near Madison Street. This was, at the time, a fashionable neighborhood. Here, he was neighbors with many prominent Chicagoans, including Matthew Laflin. Shortly after living here, he built a house at the northwest corner of Wabash Avenue and Jackson Street.

Sometime between 1856 and 1859, Bryan settled in Cottage Hill, Illinois (modern-day Elmhurst), building a 1,000-acre estate there named "Byrd's Nest". While he awaited the completion of this residence, he and his family lived in Cottage Hill's Hill Cottage Tavern, where he befriended the artist George Peter Alexander Healy. Healy would be a lifelong friend, and in 1857 bought the Hill Cottage from Barbour to serve as a residence for his own family, making them neighbors.

Once completed, the Byrd's Nest estate included a 21 room manor, a separate garden house, and a man-made lake. Living there, he would commute daily to Chicago on the Chicago and North Western Railway. In the 1860 United States census, Bryan was recorded to be the wealthiest person in DuPage County, with a net worth said to exceed $325,000. In 1864, he would sell 26 acres of his land to his brother-in-law Jedediah Hyde Lathrop, who built his own estate named "Huntington" on the site.

Bryan would ultimately play an important role in the development of the town of Cottage Hill/Elmhurst. He is often referred to as "The Father of Elmhurst". In 1860, Bryan converted the bowling alley in his Byrd's Nest residence's basement into a chapel space where he invited local residents to hold services. He did so in response to news that a former church building in the city of Chicago was being converted into bowling alley. The chapel was one of the community's first church spaces, and it proved popular enough that he was motivated five years later to erect a separate building on his estate housing a new chapel. The 1865 Byrd's Nest chapel stood where the intersection of Cottage Hill Avenue and St. Charles Road is today. It was demolished in 1914, but its former congregation is a precursor to the town's Church of Our Savior which continues to exist. In 1869, Bryan assembled a number of Cottage Hill residents and proposed the idea of renaming the community to "Elmhurst", a name reflective of the German heritage of many town residents and the many elm trees that Bryan had planted across the community over the course of the preceding ten years. This proposal was successful. That same year, Bryan and his wife Jennie sold 30 acres of their land in Elmhurst to the German Evangelical Synod of the Northwest for $10,000. In 1871, the Synod established the Elmhurst Pro-seminary on the property, a seminary which would eventually become Elmhurst University.

In 1860, Bryan established Chicago's Graceland Cemetery in partnership with William Butler Ogden, Sidney Sawyer, Edwin H. Sheldon, and George Peter Alexander Healy. He had been motivated to establish a new cemetery after being disappointed by the "neglected and actually repulsive condition" of Chicago's City Cemetery when his son Daniel was buried there. He sought to create a "rural burying ground, more remote from and worthy of the city [of Chicago]." However, he placed these ambitions on hold after Rosehill Cemetery was opened by a group independent of Bryan's efforts. However, after he was offered the presidency of the company that operated Rosehill Cemetery, Bryan became motivated to pursue his shelved plans to establish his own cemetery. He then got to work, becoming the inaugural president of the Graceland Cemetery Association. Healy served as treasurer. He purchased land for his cemetery from the heirs of Justin Butterfield, collaborated with a number of landscape architects to design the cemetery, and fought challenges from the owners of adjacent properties who opposed his plans to transform the site into a cemetery. In April 1860, the first burial at Graceland Cemetery occurred when Bryan had his late son Daniel reinterred there. Graceland Cemetery was formally dedicated that August.

1860 also saw the opening of Bryan Hall, a music hall which Bryan constructed in Chicago on Clark Street across from the city's courthouse. With a capacity of between 500 and 600 people, it was reported to be the largest hall of its kind in the metropolitan area at the time of its opening. It would remain the city's primary venue until the opening of Crosby's Opera House.

Bryan was, twice, reluctantly a nominee for mayor of Chicago. In 1861, Bryan was the People's Ticket nominee for mayor of Chicago. He lost the election to Republican Julian Sidney Rumsey by a sizable margin. Bryan had been drafted for mayor by a number of acquaintances to run on what the being dubbed "The People's Ticket". Unaware at the time that he'd be running in opposition to the Republican Party, Bryan reluctantly accepted. He was reported to, ultimately, have seemed somewhat relieved by his ultimate defeat in the polls. He did not desire to be mayor of the city, nor did he want to cause disarray or fractures in the Republican Party at the time that the Civil War was beginning. Bryan was the National Union (Republican) nominee for the office in 1863, losing by an incredibly narrow margin to incumbent mayor Francis Cornwall Sherman. He originally planned to contest the result over allegations of election fraud by the Democrats, but ultimately did not, not being concerned enough with the results, having been a reluctant candidate to begin with.

A strong unionist, during the American Civil War, Bryan funded a company of the 105th Infantry Regiment of Illinois Volunteers in the Civil War, named the "Bryan's Blues". He was a member of the Union Defense Committee. He was also president of the Northwestern Sanitary Fair, an event held in 1865 along the Chicago lakefront which raised more than $300,000 for Union soldiers. Interestingly, his wife had incidentally been in the company of Confederate Army general Robert E. Lee, a relative of hers by marriage, just days before the breakout of the Civil War.

Bryan served in leadership roles for numerous Chicago organizations. From 1865 until 1906, Bryan served as president of the Chicago Soldiers' Home, which he also had helped to found. He was president of the Union League Club of Chicago.

In 1870, Bryan leased Bryan Hall to Richard M. Hooley for a period of five years, for $21,000 per year. It was renamed the Hooley Opera House.

In the Great Chicago Fire of 1871, Bryan lost $2 million, with one significant part of this being the loss of his music hall in the fire. After the fire, he provided a number of people displaced with refuge at Byrd's Nest. Bryan was involved in helping revive the city after the fire. Shortly before the fire Bryan had founded the Federal Savings Bank and Safe Depository, also known as the Fidelity Safe Depository. Despite the burning of its building, the vaults and safes were intact, and their contents survived the fire. Bryan rebuilt a new structure for the institution quickly after the fire. He purchased the metal from the Chicago Court House Bell which he used to fashion an alarm for his company, selling the rest to H.S. Everhart & Company which commissioned the U.S. Mint to strike commemorative medals from the metal.

From December 3, 1877, through July 1, 1878, Bryan served as Commissioner of the District of Columbia. During this brief period, he and his wife briefly lived in Washington, D.C.

In 1878, Bryan stepped-down as president of Graceland Cemetery, turning over the presidency to his nephew Bryan Lathrop.

For a period of time, he and his wife moved to Colorado. At the time of the 1880 United States census, he was recorded as residing in Clear Creek County, Colorado. In the later 1880s, Bryan located his personal officers in Chicago's Home Insurance Building.

Bryan was a leading figure in the effort to bring the World's Columbian Exposition to Chicago. Bryan convinced the Chicago City Council to pass legislation that would help the city in its efforts secure the world's fair. In 1890, he, alongside Chicago mayor DeWitt Clinton Cregier and former Illinois Central Railroad president Edward Turner Jeffery, gave the presentation for Chicago's bid to the fifteen member United States Senate committee that decided what location would be awarded the fair. Bryan's remarks were perhaps the most persuasive of the three speaking on behalf of the city. In his remarks Bryan, in part, retorted the hyperbolic and critical remarks about Chicago that had been issued by Chauncey Depew (who was representing New York City's interest in receiving the fair).

After Chicago landed the fair, Bryan was appointed a commissioner-at-large of the World's Columbian Exposition Board created by federal legislation. He was ultimately the vice president of the World's Columbian Exposition, vice president of the World's Congress Auxiliary, Commissioner General of the Exposition and the Chairman of the Congresses Committee of Organization, and President of the World's Congress. Bryan worked successfully to convince the Chicago City Council, Illinois General Assembly and United States legislature to pass legislation providing assistance to the fair's organizers. In his travels through Europe promoting the exposition, he met with many ruling monarchs and Pope Leo XIII. During the exposition, he personally hosted many of the dignitaries and royals that attended the fair at his Byrd's Nest estate.

At the same time that he was organizing the world's exposition, Bryan fell victim to what ultimately turned out to be a scam run by H. H. Holmes, a man who was later discovered to be a serial killer. He lost more than $9,000 after becoming involved in a copier machine business with Holmes at the advice Bryan's associate Fred Nind. Holmes had paid Bryan a $7,000 promissory note to acquire a 51% stake in the venture from Bryan. Holmes never followed through with any cash compensation to Bryan. This was one of the largest amounts which Holmes was able to financially defraud any individual of in his long career of fraud. Holmes would go on to fraudulently use Bryan's name on the papers of this company and a number of other scam ventures companies.

Bryan was widowed on March 5, 1898, when his wife of 48 years, Jennie, died at the age of 68 at their Byrd's Nest estate of paralysis that had impacted her brain and vocal organs, before reaching her heart. She had only developed the paralysis days earlier on March 3.

Bryan spent his last decade splitting time between Byrd's Nest and living out east, in Virginia and Washington, D.C. Bryan died January 26, 1906, in Washington, D.C.

Bryan is buried at Oak Hill Cemetery in Washington, D.C., where the Bryan family had a burying ground. His wife Jennie had been buried at Oak Hill Cemetery after her 1898 death. His son Charles would be buried in the cemetery after his death in 1918, as would his daughter Jennie after her death in 1919 and his son-in-law John Barton Payne after his death in 1935.

After his death, ownership of the Byrd's Nest estate passed to his son, Charles. However, Charles rarely lived there due to his service as a diplomat. In 1920, the estate was given to a charitable organization for the purposes of serving as an orphanage. After this proved unsuccessful, the estate was sold to a real estate developer in 1924 and was subsequently subdivided for residential development. No physical remnants remain of the estate that Bryan had built.

Bryan commissioned many works by George Peter Alexander Healy. The two had become friends around the time Bryan moved to Cottage Hill (Elmhurst). In 1857, Healy purchased the Hill Cottage (a cottage in Cottage Hill) from Bryan, where Healy lived for next six years. This made him neighbors with Bryan during this period. Healy created a number of paintings of the Bryan family. He also partnered with Bryan in the founding of Graceland Cemetery. In addition, Bryan's daughter Jennie became a student of Healy's. On one occasion in 1860, Bryan purchased all the paintings Healy's entire inventory of Heale's painting gallery to and displayed the works in a hall that he owned on Dearborn Street.

In Bryan's art collection were portraits which Henry Clay, Edward Everett, Henry Wadsworth Longfellow, Daniel Webster had posed for. Bryan also owned a collection of paintings of all presidents of the United States, many of which had been painted by Healy. Bryan gave his collection of presidential portraits to the Corcoran Gallery of Art.

After Bryan's death, many of the paintings of Healy's that he still owned were passed on to his daughter Jennie. After her death in 1919, in 1920, Jennie Byrd's Payne's widowed husband, John Barton Payne, gave a collection of forty masterpieces to the State of Virginia, a gift valued at time at over $1 million. In this gift were several paintings Bryan commissioned from Healy. This gift, which was given by Payne alongside a financial gift of $100,000 for a museum to house the art, came with a stipulation that the state must match his gift. This was eventually done in 1932, and construction began on the Virginia Museum of Fine Arts.

In his life, Bryan acquired several noteworthy pieces of historic memorabilia.

After the Great Chicago Fire, Bryan purchased the broken remains of the bell from the city's lost courthouse at an auction. He kept parts of the bell, but sold most of the bell's remains to H.S. Everhart & Company, who made one-inch tall miniature bells as souvenirs. The courthouse bell was notable in relation to the fire, as it had been one of the bells in the city that was rung to warn citizens of the fire.

After notable people had been invited to send items to the Northwestern Sanitary Fair to auction, Abraham Lincoln sent the original handwritten draft of the Emancipation Proclamation. Bryan was successful in bidding for it, paying $3,000 for it, the item being the highest bid item on auction. Bryan had lithographic copies made and sold for the benefit of the Sanitary Commission. Bryan gifted the document to the Chicago Soldier's Home, who in turn entrusted it to the Chicago Historical Society for safekeeping. However, this original document was lost in the Great Chicago Fire.

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