The Little Tennessee River rises in the Blue Ridge Mountains, in the Chattahoochee National Forest in northeast Georgia's Rabun County.

The lower river is impounded in several places by sequential dams, some created as part of the Tennessee Valley Authority (TVA) system.

The proposed project to build the dam and reservoir was the subject of environmental controversy during the 1970s because of the discovery of the snail darter, an endangered species.

The Little Tennessee River and its immediate watershed comprise one of the richest archaeological areas in the southeastern United States, containing substantial indigenous habitation sites dating to as early as 7,500 B.C.

[9] Cyrus Thomas, who conducted a survey in the 1880s of earthwork mounds in the area for the Smithsonian Institution, wrote that the Little Tennessee River was "undoubtedly the most interesting archaeological section in the entire Appalachian district.

[11] These sites were probably semi-permanent base camps, the inhabitants of which may have sought the chert deposits on the bluffs above the river which they used to create tools.

Salvage archeological excavations in the 1970s before completion of the Tellico Dam uncovered large groups of Woodland-period burials on both Rose and Calloway islands in present-day Tennessee.

As noted above, the river was the spine of most of the major Overhill Cherokee towns, the most prominent of which included Chota, Tanasi, Toqua, Tomotley, Mialoquo (near Rose Island), Chilhowee (at the river's Abrams Creek confluence), Tallassee (near modern Calderwood), Citico, and Tuskegee (adjacent to Fort Loudoun).

[20] The Hazel Creek section of the Great Smoky Mountains National Park, located on the north shore of the river's Fontana Lake impoundment, was home to a substantial European-American Appalachian community in the late 19th and early 20th centuries.