Before the arrival of Europeans to the area, The Smoky Mountains were in the area settled by the Cherokee Nation, a peaceful tribe that did extensive farming. Cherokee Indians lived from Ohio to South Carolina and from northern Georga to North Carolina. The Cherokee Indians discourage settlers from entering the area until after the Revolutionary War, when they allied with the British. In an effort to gain peace, the Cherokee allowed settlers and adapted to the new ways of the settlers, building modern houses, attending school, and by 1820 they created a written language.

The area of Cades Cove was the first settlement within what is now the National Park, established in 1818. Many of the structures in Cades Cove have been preserved and the area is the most visited in the Park. Despite the accomodations made by the Cherokee, the settlers were insistent upon the Indians being moved west of the Mississip river. When Gold was discovered on Indian lands, the Federal Government ordered the Indians to be moved. Only a few Cherokee that chose to hide in The Smoky Mountains remained behind, with 14,000 Indians being escorted to Oklahoma in 1838. This journey was known as "the Trail of Tears," with only 10,000 survivors of the trip.

Although no slaves ever worked Cades Cove and many of the residents had close ties to the North, the town had soldiers on both sides of the Civil War. From 1862-1864, a Confederate regiment terrorized the Northern leaning Cove by stealing livestock, harassing children, and taking prisoners. Small children guarded the mountain tops, blowing horns when the Confederates approached. The people of the Cove felt abandoned by the North after the war and did not trust or welcome outsiders, resulting in a stoppage of immigration to the area until the logging industry came to The Smoky Mountains aroud 1900.

In the 1920's, the Park Service began buying land to form the Smoky Mountain National Park. About half of the residents of Cades Cove accepted the offer to sell their land, the other residents resisted selling and case went to Tennesses State Supreme Court. A compromise was reached, with the residents allowed to live on their land with a lifetime lease. One family remains in Cades Cove currently.