The Tennessee River is the largest tributary of the Ohio River. It is approximately 652 miles (1,049 km) long and is located in the southeastern United States in the Tennessee Valley. The river was once popularly known as the Cherokee River, among other names, as the Cherokee people had their homelands along its banks, especially in what are now East Tennessee and northern Alabama. Additionally, its tributary, the Little Tennessee River, flows into it from Western North Carolina and northeastern Georgia, where the river also was bordered by numerous Cherokee towns. Its current name is derived from the Cherokee town, Tanasi, which was located on the Tennessee side of the Appalachian Mountains.

The river appears on French maps from the late 17th century with the names "Caquinampo" or "Kasqui." Maps from the early 18th century call it "Cussate," "Hogohegee," "Callamaco," and "Acanseapi." A 1755 British map showed the Tennessee River as the "River of the Cherakees." By the late 18th century, it had come to be called "Tennessee," a name derived from the Cherokee village named Tanasi.

The Tennessee River is formed at the confluence of the Holston and French Broad rivers in present-day Knoxville, Tennessee. From Knoxville, it flows southwest through East Tennessee into Chattanooga before crossing into Alabama. It travels through the Huntsville and Decatur area before reaching the Muscle Shoals area, and eventually forms a small part of the state's border with Mississippi, before returning to Tennessee. The river misses Georgia by about 250 feet (76 m). The Tennessee River's route northerly through Tennessee defines the boundary between two of Tennessee's Grand Divisions: Middle and West Tennessee.

The Tennessee–Tombigbee Waterway, a U.S. Army Corps of Engineers project providing navigation on the Tombigbee River and a link to the Port of Mobile, enters the Tennessee River near the Tennessee-Alabama-Mississippi boundary. This waterway reduces the navigation distance from Tennessee, north Alabama, and northern Mississippi to the Gulf of Mexico by hundreds of miles. The final part of the Tennessee's run is north through western Kentucky, where it separates the Jackson Purchase from the rest of the state. It flows into the Ohio River at Paducah, Kentucky.

The river valley was once home to several Native American tribes. At Painted Bluff, in northeast Alabama, painted glyphs dating to ca. 1400 A.D. have been discovered among cliffs overlooking the river.

The first major battles of the American Civil War occurred along the river in 1862. The commander in the western theater, General Henry Halleck, considered the Tennessee River to be more significant than the Mississippi.

The Tennessee River begins at mile post 652, where the French Broad River meets the Holston River, but historically there were several different definitions of its starting point. In the late 18th century, the mouth of the Little Tennessee River (at Lenoir City) was considered to be the beginning of the Tennessee River. Through much of the 19th century, the Tennessee River was considered to start at the mouth of Clinch River (at Kingston). An 1889 declaration by the Tennessee General Assembly designated Kingsport (on the Holston River) as the start of the Tennessee, but the following year a federal law was enacted that finally fixed the start of the river at its current location.

At various points since the early 19th century, Georgia has disputed its northern border with Tennessee. In 1796, when Tennessee was admitted to the Union, the border was originally defined by United States Congress as located on the 35th parallel, thereby ensuring that at least a portion of the river would be located within Georgia. As a result of an erroneously conducted survey in 1818 (ratified by the Tennessee legislature, but not Georgia), however, the actual border line was set on the ground approximately one mile south, thus placing the disputed portion of the river entirely in Tennessee.

Georgia made several unsuccessful attempts to correct what Georgia felt was an erroneous survey line "in the 1890s, 1905, 1915, 1922, 1941, 1947 and 1971 to 'resolve' the dispute", according to C. Crews Townsend, Joseph McCoin, Robert F. Parsley, Alison Martin and Zachary H. Greene, in their May 12, 2008, article for the Tennessee Bar Journal, a publication of the Tennessee Bar Association.

In 2008, as a result of a serious drought and resulting water shortage, the Georgia General Assembly passed a resolution directing the governor to pursue its claim in the United States Supreme Court.

According to a story aired on WTVC-TV in Chattanooga on March 14, 2008, a local attorney familiar with case law on border disputes, said the U.S. Supreme Court generally will maintain the original borders between states and avoid stepping into border disputes, preferring the parties work out their differences.

The Chattanooga Times Free Press reported on March 25, 2013, that Georgia senators approved House Resolution 4 stating that if Tennessee declines to settle with them, the dispute will be given to the state attorney general, to take Tennessee before the Supreme Court to settle the issue once and for all. The Atlantic Wire, in commenting on Georgia's actions stated:

"The Great Georgia-Tennessee Border War of 2013 Is Upon Us Historians, take note: On this day, which is not a day in 1732, a boundary dispute between two Southern states took a turn for the wet. In a two-page resolution passed overwhelmingly by the state senate, Georgia declared that it, not its neighbor to the north, controls part of the Tennessee River at Nickajack. Georgia doesn't want Nickajack. It wants that water.".

The Tennessee River is an important part of the Great Loop, the recreational circumnavigation of Eastern North America by water. The main channel is accessible to recreational watercraft at over 200 public access points along the river's course.

The Tennessee River has historically been a major highway for riverboats through the South, and today they are frequently used along the river. Major ports include Guntersville, Chattanooga, Decatur, Yellow Creek, and Muscle Shoals. This river has contributed greatly to the economic and industrial development of the Tennessee Valley as a whole. The economies of cities such as Decatur and Chattanooga would not be as dynamic as they are today, were it not for the Tennessee River. Many companies still rely on the river as a means of transportation for their materials. In Chattanooga, for example, steel is exported on boats, as it is much more efficient than moving it on land.

In addition, locks along the Tennessee River waterway provide passage between reservoirs for more than 13,000 recreational craft each year. The Chickamauga Dam, located just upstream from Chattanooga, is projected to have a new lock built, but it has been delayed due to a lack of funding. The river not only has many economic functions, such as the boat building industry and transportation, but it also provides water and natural resources to those who live near the river. Many of the major ports on the river are connected to a settlement that was started because of its proximity to the river.

On October 15, 2022, the University of Tennessee Volunteers football team defeated the University of Alabama Crimson Tide 52–49 at Neyland Stadium in Knoxville, Tennessee, on a game-winning field goal by Chase McGrath as time expired. In celebration of this victory, the fans stormed the field, tore down the goalposts, and threw them into the Tennessee River after an impromptu parade in which fans carried the goalposts around the city of Knoxville.

The river has been dammed numerous times since the 1930s by Tennessee Valley Authority (TVA) projects. The construction of TVA's Kentucky Dam on the Tennessee River and the Corps of Engineers' Barkley Dam on the Cumberland River led to the development of associated lakes, and the creation of an area called the Land Between the Lakes. A navigation canal located at Grand Rivers, Kentucky, links Kentucky Lake and Lake Barkley. The canal allows for a shorter trip for river traffic going from the Tennessee to most of the Ohio River, and for traffic going down the Cumberland River toward Tennessee.

The Tennessee River and its tributaries host some 102 species of mussel. Native Americans ate freshwater mussels. Potters of the Mississippian culture used crushed mussel shell mixed into clay to make their pottery stronger.

A "pearl" button industry was established in the Tennessee Valley beginning in 1887, producing buttons from the abundant mussel shells. Button production ceased after World War II when plastics replaced mother-of-pearl as a button material. Mussel populations have declined drastically due to dam construction, water pollution, and invasive species.

Tributaries and sub-tributaries are listed hierarchically in order from the mouth of the Tennessee River upstream.

• Woodside, M.D. et al. (2004). Water quality in the lower Tennessee River Basin, Tennessee, Alabama, Kentucky, Mississippi, and Georgia, 1999–2001 [U.S. Geological Survey Circular 1233]. Reston, VA: U.S. Department of the Interior, U.S. Geological Survey.
• Myers, Fred (2004). Tennessee River CruiseGuide, 5th Edition
• Hay, Jerry (2010). Tennessee River Guidebook, 1st Edition
• Rumsey, W.J. (2007). A Cruising Guide to the Tennessee River, Tenn-Tom Waterway, and Lower Tombigbee River

• Tennessee Rivers
• Map of Tennessee River in Alabama
• Tennessee River Navigation Charts
• Chickamauga dam progress
• Works related to Tennessee River at Wikisource