The area is part of the large historic Cherokee territory in the Southeast, which extended into eastern Tennessee, western South Carolina, northern Georgia, and Alabama.

Currently, the largest contiguous portion of the Qualla lies in Haywood, Swain, and Jackson counties and is centered on the community of Cherokee, which serves as the tribal capital of the EBCI.

The main part of the Qualla Boundary lies in eastern Swain and northern Jackson counties (just south of Great Smoky Mountains National Park).

During their colonial expansion west, European settlers sometimes came into conflict with the Cherokee, whose territory extended into present-day Tennessee and northern Georgia.

After the late 18th century and warfare with American settlers during and after the Revolutionary War, many of the Cherokee moved farther south along the Tennessee River, into Georgia and westward into Alabama, establishing at least eleven new towns [citation needed].

During the winter of 1838 and early the spring of 1839, the U.S. Federal Government relocated approximately 11,000 Cherokee from their homeland in North Carolina, in what is known as the Trail of Tears.

[10] In the 1930s, the federal government requested the tribe to cede land for the construction of a new motorway, called the Blue Ridge Parkway, that would cut through the Qualla Boundary to end at the Great Smoky Mountains National Park.

[13] The tribal community functions like most municipalities, operating schools, law enforcement, and rescue services, in addition to their own hospital and gaming casino, known as Harrah's Cherokee.

It replaced these with elementary day schools, located closer to students' homes in Big Cove, Soco, Birdtown, and Snowbird.

[26] In 2004, the EBCI established the New Kituwah Academy, a private bilingual Cherokee-English language immersion school for Cherokee students in kindergarten through sixth grade, located in the Yellowhill community.

[27] In 1975 Western Carolina University opened its Cherokee Center in cooperation with the EBCI, which is the headquarters for outreach and involvement between residents in the Qualla Boundary and outside surrounding communities.

It provides services including application process, transcript request, scholarships, internships placement, high school recruitment, as well as college level courses.