The first European settlement in what is now Pendleton County was established by 1740 near Cherry Grove. By 1747, several families, mostly of German descent, had settled at Fort Seybert and Upper Tract. German culture remained strong in the area well into the 1900s. The region, part of Augusta County at the time, faced Indian attacks during the French and Indian War, with Shawnee raids in 1758 that destroyed Forts Upper Tract and Seybert. However, Hinkle's Fort survived. During the American Revolution, the community had divided loyalties, with some tories supporting the British.

From 1790 to 1860, Pendleton's population grew from 2,452 to 6,164, with 50 free Blacks and 244 enslaved people. Franklin, originally called Frankford, was chartered in 1794. In 1821, Pendleton lost land to Pocahontas County, and in 1847, part of Pendleton became Highland County, Virginia. Pendleton's borders have stayed the same since then. During the War of 1812, the niter and gunpowder industry, especially at Trout Rock caves, was important. For almost 100 years, Pendleton's stockmen were part of the South Branch's successful cattle industry.