The Tennessee River Valley was first inhabited by generations of Native Americans, and Meigs County contains many prehistoric and Cherokee sites. Hiwassee Island, at the mouth of the Hiwassee River, is the site of a large Mississippian Period town dating from the 11th century A.D. Before 1819 treaties ceded large swaths of land to Tennessee, Meigs County was part of the Cherokee Nation. In 1838, most of the Cherokee people were forcibly removed from the area as part of the Trail of Tears. Today, the Cherokee Removal Memorial Park at Blythe Ferry marks this tragic period of history.  

The first settlements in Meigs County were in the Ten Mile area, while later families settled near the site of Decatur. Early commerce was linked to riverboats at landings such as Cottonport, Pinhook and Breedenton. Several ferries were also established: the Blythe, Washington, and Free ferries on the Tennessee River, and the Russell and Kincannon ferries on the Hiwassee River. In the 1990s, two bridges replaced the Blythe and Washington ferries, the last ferries in the eastern Tennessee River Valley.