Native Americans, mostly members of the federally recognized Eastern Band of Cherokee Indians, comprise 29% of the population in Swain County.

This area was occupied for thousands of years by cultures of indigenous peoples, who successively settled in the valleys of the three rivers and their tributaries.

During the Woodland and South Appalachian Mississippian culture period, the latter beginning about 1000 CE, the peoples built earthwork platform mounds as their central public architecture.

The earliest European explorers, including two Spanish expeditions of the mid-to-late 16th century, are believed to have encountered Mississippian chiefdoms in some parts of the interior of the Southeast.

The historic Cherokee people emerged as a culture, and they became the primary occupants of a large homeland taking in what is now known as western Virginia, western North and South Carolina, southeastern Tennessee, northeast Georgia and northern Alabama.

The Eastern Band of Cherokee Indians (EBCI) acquired the Kituwa mound and former town site in 1996, and preserve it as sacred ground.

Under President Andrew Jackson, Congress passed the Indian Removal Act of 1830, to force the Five Civilized Tribes out of the Southeast.

He used federal army forces to round up and accompany most of the Cherokee to Indian Territory west of the Mississippi River (the area was later admitted in 1907 as the state of Oklahoma).

It was not organized by European Americans until 1871 during the Reconstruction era, when it was formed from parts of Jackson and Macon counties.

In 1868 the federal government recognized the Eastern Band of Cherokee Indians, made up of people who had stayed at the time of removal and their descendants.

It holds more of the Great Smoky Mountains National Park than any other county in North Carolina or Tennessee.

As of 2024, Swain County has 3,930 acres of agricultural land – the fourth-lowest amount in the state.

Swain has voted Republican the last six Presidential elections, but historically has been a swing county, with no candidate from either major party obtaining under 37 percent of the county's vote between 1976 and 2012, and no margin larger than twelve percentage points occurring in any election between 1984 and 2012.

Swain was solidly Democratic during the Third Party System, but the Populist movement dramatically increased the success of progressive Republicans between 1896 and 1928.

However, the victory in the county of Progressive Party candidate Theodore Roosevelt in 1912 and subsequent dominance of liberal Democrats like Franklin D. Roosevelt and Adlai Stevenson suggest that the county's voters were drawn more to the relatively progressive agendas of these candidates than they were to any party label.

This was conditional on the adoption of a tribal-state gaming compact agreed to by both the tribe and the state, as well as approved by the federal government.