Evidence indicates that the Cherokee migrated in prehistoric times from present-day Texas or northern Mexico to the Great Lakes area. However, wars with the Iroquois and Delaware tribes, who controlled those lands, pushed the Cherokee southeast to the mountains and valleys of the southern part of the Appalachian chain. They eventually settled in modern Virginia, West Virginia, North Carolina, Tennessee, Georgia, and Alabama.

The Cherokee economy, like that of other Southeast tribes, was based primarily on agriculture, growing corn, beans, squash, sunflowers and tobacco. Deer, bear, and elk were hunted with bows and arrows. Smaller game, such as raccoons, rabbits, squirrels, and turkeys, were hunted with long cane-stem blowguns that propelled wood-and-feather darts. For fishing, hooks and lines, spears, and traps were used. Wild plant foods, including roots, greens, berries and nuts were also gathered for another source of nutrition.

The Cherokee women wore skirts woven from plants, while the men wore breechcloths or leggings. The men would paint their skin and decorate it with tattoos. The women would sew feathers into light capes made of netting.

The Cherokee were divided into seven matrilineal clans who lived in numerous permanent villages, typically placed along rivers and streams. Cherokee families typically had two dwellings: rectangular summer houses with cane and clay walls and bark or thatch roofs, and cone-shaped winter houses with pole frames and brushwork covered by mud or clay. The Cherokee crafted pottery as well as baskets.

The Spanish explorer, Hernando de Soto, first encountered them in the Appalachians in 1540. By 1715 smallpox had reduced the Cherokee population to about 11,000.

During the British and French struggle for control of colonial North America, the Cherokee provided warriors in support of the British, but revolted against them in 1760 in the Cherokee War under Chief Oconostota.  During the American Revolution tribal members aided Great Britain with sporadic attacks on outlying settlements, as the pioneers continually encroached upon Cherokee lands.

In 1785 a number of bands negotiated a peace treaty with the United States, but Cherokee resistance continued for a decade thereafter. In 1791 a new treaty reconfirmed the earlier one; part of Cherokee territory was ceded to the United States, and the permanent rights of the tribe to the remaining territory were established. Between 1790 and 1819, several thousand of the tribe began to leave their lands, becoming known as the Chickamauga. Led by Chief Dragging Canoe, the Chickamauga made alliances with the Shawnee and engaged in raids against colonial settlements, aided by the British.