Pontiac's Rebellion, an uprising against settlers in the Ohio Valley and Great Lakes region, followed the French and Indian War's conclusion in 1763. Western Virginians were among those to suffer.

Pontiac (about 1720—69) was a member of the Ottawa tribe and recognized as a leader within that group by the mid-1750s. Pontiac accepted the teaching of Neolin, a militant prophet of the Delaware tribe, who argued that whites and Indians originated from different creators and that Indians must align to expel whites, particularly the English, or suffer cultural disintegration. As allies of the French during their losing seven-year struggle with Great Britain, western tribes had engaged in extensive cooperation among themselves, a basis for further collaboration. When Pontiac realized that an English victory meant not only occupation of French trading centers but also waves of settlers dispossessing Indians of land, he quickly joined the message of the prophet with his own charismatic appeal to forge a military alliance among elements of the Ottawa, Delaware, Kickapoo, Miami, Potawatomi, Seneca, Shawnee, and Wyandotte.

Pontiac instructed Indians to feign friendship, gain entrance to all western British forts, kill the soldiers, and then slaughter helpless nearby settlers. Coordinated attacks commenced in the spring of 1763, eradicating most fortifications. The largest of those that survived were Detroit and Fort Pitt. In Western Virginia's Greenbrier region, the Shawnee chief Cornstalk led approximately 60 warriors who posed as friends to white residents they encountered and then murdered them. Dozens of whites died as a result of these tactics. In August, George Washington outlined plans to defend western Virginia by stationing 500 Virginia militiamen on the western frontier.

Pontiac himself directed the assault upon Detroit, but an informer warned the garrison, forcing the Indians to mount a siege. The fort withstood the siege and British countermeasures ultimately forced Pontiac to negotiate peace in 1766 in Detroit after unsuccessfully attempting to convince tribes along portions of the Mississippi River to join the Indian alliance. While visiting near what is now Caholia, Illinois, Pontiac died when knifed by another Indian.