The Little Tennessee River and its immediate watershed comprise one of the richest archaeological areas in the southeastern United States, containing substantial habitation sites dating back to as early as 7,500 B.C.  Cyrus Thomas, who conducted a survey of earthwork mounds in the area for the Smithsonian Institution in the 1880s, wrote that the Little Tennessee River was "undoubtedly the most interesting archaeological section in the entire Appalachian district."

Substantial Archaic period (8000-1000 B.C.) sites along the river include the Icehouse Bottom and the Rose Island sites, both located near the river's confluence with the Tellico River.
 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.

Evidence of Woodland period (1000 B.C. - 1000 A.D.) habitation has been uncovered at numerous sites along the Little Tennessee, most notably at Icehouse Bottom, Rose Island, Calloway Island (near the river's confluence with Toqua Creek), Thirty Acre Island (near the river's confluence with Nine Mile Creek) and Bacon Bend (between Toqua and Citico Beach).
 Excavations in the 1970s uncovered large groups of Woodland-period burials on both Rose and Calloway islands.
 Pottery fragments uncovered at Icehouse Bottom in the 1970s show evidence of interaction with the Hopewell people of what is now Ohio.

Mississippian period (c. 1000-1500 A.D.) sites in the Little Tennessee Valley include the Toqua site (at the river's confluence with Toqua Creek), Tomotley (adjacent to Toqua), Citico (at the river's Citico Creek confluence), and Bussell Island (at the mouth of the river).
 Toqua's Mississippian inhabitants constructed a 25-foot (7.6 m) platform mound overlooking a central plaza.
 By 1400, the village covered 4.8 acres (0.019 km²) surrounded by a clay-covered palisade.


Several Cherokee Middle towns, including Nikwasi, Jore, and Cowee were located along the river's North Carolina section.
 The river was also home to 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).

Euro-American traders were visiting the Overhill towns along the Little Tennessee by the late 17th century, and there is some evidence that Hernando De Soto and Juan Pardo passed through the Little Tennessee Valley in 1540 and 1567, respectively.
 In 1756 the English built Fort Loudoun, located at the river's confluence with the Tellico River.
 The fort has been reconstructed as an historic site.
 Two early American sites are located along the Little Tennessee— the Tellico Blockhouse, an outpost at the river's Nine Mile Creek confluence, and Morganton, a river port and ferry town near modern Greenback that thrived in the early 19th century.
 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 Appalachian community in the late 19th and early 20th centuries.
The Little Tennessee River and its immediate watershed comprise one of the richest archaeological areas in the southeastern United States, containing substantial habitation sites dating back to as early as 7,500 B.C.  Cyrus Thomas, who conducted a survey of earthwork mounds in the area for the Smithsonian Institution in the 1880s, wrote that the Little Tennessee River was "undoubtedly the most interesting archaeological section in the entire Appalachian district."
Substantial Archaic period (8000-1000 B.C.) sites along the river include the Icehouse Bottom and the Rose Island sites, both located near the river's confluence with the Tellico River.  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.
Evidence of Woodland period (1000 B.C. - 1000 A.D.) habitation has been uncovered at numerous sites along the Little Tennessee, most notably at Icehouse Bottom, Rose Island, Calloway Island (near the river's confluence with Toqua Creek), Thirty Acre Island (near the river's confluence with Nine Mile Creek) and Bacon Bend (between Toqua and Citico Beach).  Excavations in the 1970s uncovered large groups of Woodland-period burials on both Rose and Calloway islands.  Pottery fragments uncovered at Icehouse Bottom in the 1970s show evidence of interaction with the Hopewell people of what is now Ohio.
Mississippian period (c. 1000-1500 A.D.) sites in the Little Tennessee Valley include the Toqua site (at the river's confluence with Toqua Creek), Tomotley (adjacent to Toqua), Citico (at the river's Citico Creek confluence), and Bussell Island (at the mouth of the river).  Toqua's Mississippian inhabitants constructed a 25-foot (7.6 m) platform mound overlooking a central plaza.  By 1400, the village covered 4.8 acres (0.019 km²) surrounded by a clay-covered palisade.

Several Cherokee Middle towns, including Nikwasi, Jore, and Cowee were located along the river's North Carolina section.  The river was also home to 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).
Euro-American traders were visiting the Overhill towns along the Little Tennessee by the late 17th century, and there is some evidence that Hernando De Soto and Juan Pardo passed through the Little Tennessee Valley in 1540 and 1567, respectively.  In 1756 the English built Fort Loudoun, located at the river's confluence with the Tellico River.  The fort has been reconstructed as an historic site.  Two early American sites are located along the Little Tennessee— the Tellico Blockhouse, an outpost at the river's Nine Mile Creek confluence, and Morganton, a river port and ferry town near modern Greenback that thrived in the early 19th century.  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 Appalachian community in the late 19th and early 20th centuries.
Little Tennessee River