Indigenous cultures of Native Americans have been living and hunting along the Tuckasegee River in the vicinity of what is now Bryson City for nearly 14,000 years.

In 1567, an orata (minor chief) from Kituwa is believed to have met with Spanish explorer Juan Pardo in the French Broad Valley to the north.

American soldiers burned and destroyed the town of Kituwa in 1776, but the Cherokee continued to hold annual ceremonial dances at the site throughout the 19th century.

[8] Around 1818, a Cherokee chief known as Big Bear received a 640-acre (2.6 km2) reservation of land immediately west of the confluence of Deep Creek and the Tuckasegee River.

The Shulers, in turn, sold parts of their land to Colonel Thaddeus Bryson and merchant Alfred Cline.

Lucy Ann (Raby) Cline agreed to sell several lots of her land to form a county seat.

The Western North Carolina Railroad laid tracks through Bryson City in 1884, greatly improving transportation to the previously isolated area.

Horace Kephart, an author and outdoors enthusiast who was based in Bryson City for several years, was a key early proponent for creation of the park.

[11] The Deep Creek section of the park, which is immediately north of Bryson City, has a large campground and multiple trailheads.

It is also the base of the Eastern Band of Cherokee Indians, the only federally recognized tribe in North Carolina.

The completion of Fontana Dam in 1944 created a reservoir, which inundated the only highway connecting Bryson City with the remote area of the Smokies known as the North Shore.

After Norfolk Southern ended freight traffic on the railroad in 1985, the state of North Carolina purchased the tracks.

In 1988, the state established a scenic line, known as the Great Smoky Mountains Railroad, with its depot and departure point in Bryson City.

The Qualla Boundary, which comprises the bulk of the reservation of the Eastern Band of Cherokee Indians, dominates the area to the east.

Main Street is part of U.S. Route 19, which connects Bryson City to Cherokee to the northeast and Murphy to the southwest.