The Tuscarora War was fought in North Carolina from September 10, 1711 until February 11, 1715 between the Tuscarora people and their allies on one side and European American settlers, the Yamassee, and other allies on the other. This was considered the bloodiest colonial war in North Carolina. The Tuscarora signed a treaty with colonial officials in 1718 and settled on a reserved tract of land in Bertie County, North Carolina. The war incited further conflict on the part of the Tuscarora and led to changes in the slave trade of North and South Carolina.

The first successful settlement of North Carolina began in 1653. The Tuscarora lived in peace with the settlers for more than 50 years, while nearly every other colony in America was involved in some conflict with Native Americans. Most of the Tuscarora migrated north to New York after the war, where they joined the Five Nations of the Iroquois Confederacy as the sixth nation.

Fort Neoheroka (or just Neoheroka, Neyuherú·kęʼ in Tuscarora), or Nooherooka, is the name of a stronghold constructed in what is now Greene County, North Carolina by the Tuscarora tribe during the Tuscarora War of 1711–1715. In March 1713, the fort was besieged and ultimately attacked by a colonial force consisting of an army from the neighboring Province of South Carolina, under the command of Colonel James Moore and made up mainly of Indians including Yamasee, Apalachee, Catawba, and Cherokee. The 1713 siege lasted for more than three weeks, from around March 1 to March 22, 1713. Hundreds of men, women and children were burned to death in a fire that destroyed the fort. Approximately 170 more were killed outside the fort while approximately 400 were taken to South Carolina where they were sold into slavery. The defeat of the Tuscaroras, once the most powerful Indian tribe in the Province of North Carolina, opened up North Carolina's interior to further settlement. The supremacy of the Tuscaroras in the colony was broken forever, and most moved north to live among the Iroquois. On July 17, 2009, the Fort Neoheroka Site was added to the National Register of Historic Places.