The South Branch Potomac River has its headwaters in northwestern Highland County, Virginia, near Hightown along the eastern edge of the Allegheny Front.

[5] The Native Americans of the region, and thus the earliest white settlers, referred to the South Branch Potomac River as the Wappatomaka.

At Forks of Waters, the South Branch joins with Strait Creek and flows north across the Virginia/West Virginia border into Pendleton County.

Into Grant, the South Branch follows the western side of Cave Mountain through the 20-mile (32 km) long Smoke Hole Canyon, until its confluence with the North Fork at Cabins, where it flows east to Petersburg.

The South Branch is traversed by the Northwestern Turnpike (U.S. Route 50) and joined by Sulphur Spring Run where it forms Valley View Island to the west of town.

Flowing north of Romney, the river still follows the eastern side of Mill Creek Mountain until it creates a horseshoe bend at Wappocomo's Hanging Rocks around the George W. Washington plantation, Ridgedale.