Cherokee National Forest took its name from the Cherokee Indians, stewards of this land long before colonial settlers moved into what is now east Tennessee in the late 1700s. A wave of the northern timber companies moved to this region in the early 1880s. By 1910, almost 40 percent of the timber produced in the United States was harvested from the Southern Appalachian Mountains. As timber and mineral companies bought up large tracts of land, small mountain farms decreased and towns became important centers of population. Local residents were employed both in the forest and in work camps. For several years, lumbering provided steady dependable income for thousands of mountaineers. Timber was brought out of the mountains by rail and by the rivers. A rail line was built along the Tellico River in the early 1900s. Because of constant flooding, this road was moved upslope and converted to a road in the mid-1930s, and today it is the Tellico River Road (FR 210), a beautifully scenic drive (with many great fly fishing holes!).

A 1902 government report outlined the devastation of the Southern Appalachians. As a result of the report Congress passed the Weeks Act in 1911, authorizing the federal government to purchase "forested, cut-over, or denuded lands within the watersheds of navigable streams." Much of what is now known as Cherokee National Forest was acquired under this Act. Cherokee National Forest was established June 14, 1920, from land acquired in southeast Tennessee. In 1936, national forests were reorganized along state lines and all National Forest System land in Tennessee became Cherokee National Forest.

The quality of forestlands purchased during this time varied over the Southern Appalachian region. The best lands were in areas with remote, steep terrain where rail and road access was difficult. Unlike some Appalachian forests, most of the lands acquired in the Cherokee purchases were already cutover, burned, or in the process of being cut.