The Tennessee River is formed at the confluence of the Holston and French Broad Rivers on the east side of Knoxville, Tennessee. From Knoxville, it flows southwest through East Tennessee toward Chattanooga before crossing into Alabama. It loops through northern Alabama and eventually forms a small part of the state's border with Mississippi, before returning to Tennessee. At this point, it defines the boundary between Tennessee's other two regions - Middle and West Tennessee.

The Tennessee River is an important part of the America's Great Loop, the recreational circumnavigation of Eastern North America by water. The America's Great Loop Cruisers' Association assists Great Loop cruisers with various needs such as safety, sharing navigational and cruising information, and networking among loopers.

The Tennessee River's beautiful Kentucky Lake holds records for the largest of three species of fish ever taken in Kentucky: White bass, Buffalo carp, and yellow perch. It is also the major attraction for state parks in Kentucky and Tennessee: Kentucky Dam Village State Resort Park, Kenlake State Resort Park, Paris Landing State Park, and Nathan Bedford Forrest State Park.

Kentucky Lake is also the home of The Tennessee River Freshwater Pearl Farm - the only freshwater pearl culturing farm in America - Tennessee's Official State Gem.