Native Americans lived in what is now Tennessee long before Europeans arrived. Among the early inhabitants were the Cherokee, Chickasaw, Choctaw, Creek, Muscogee, and Yuchi.

The mound-building tradition was strong in this area. Among well-known remains are the Pinson Mounds, a complex of 17 mounds in Madison County that dates to before A.D. 500.

French and Spanish explorers roamed the area beginning in the 1500s. One of the Spanish expeditions featured Hernando de Soto, thought to have been the first European to have crossed the Mississippi River. The famous French explorers Jacques Marquette, Louis Jolliet, and René-Robert de La Salle moved extensively through the area in the in the mid-1600s. La Salle claimed the entire Mississippi River basin for France.

Between the French and Indian War and the Revolutionary War, English settlers moved west. Daniel Boone was one of those, helping to blaze the Wilderness Road.

Settlers lived on farms, growing corn and cotton and tobacco and wheat and keeping vegetable gardens and large numbs of livestock, among them cows, horses, mules, and pigs. Slavery was not uncommon at Tennessee farms and settlements and was more prevalent in the western part of the territory.

As well, as with other colonies, Tennessee's settlements featured other necessary trades, like blacksmith shops and lumber mills, general stores and ironworks (the largest industry in the area).

Some Native American tribes welcomed English settlers and their money and goods. Other tribes were not so welcoming, among them the Chickamauga, whose war chief, Dragging Canoe, actively resisted European settlement in a long struggle known as the Cherokee-American wars.

Some from Tennessee fought in the Revolutionary War, notably at the Battle of Kings Mountain, in South Carolina. Tennessee's John Sevier led a group of men who contributed to the Continental Army's decisive victory in that battle.

A fur trader named Charles Charleville built a trading post on the Cumberland River in the north central part of what is now Tennessee. This area became a hub of activity and was later named French Lick, after the natural salt lick that attracted animals and, in turn, hunters and traders. Settlers and traders developed the area further, building Fort Nashborough, and the area eventually became Nashville, after Francis Nash, a Revolutionary War general.

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