U.S. Route 501 is a spur of U.S. Route 1. It runs 355 miles (571 km) from Buena Vista, Virginia at U.S. Route 60 to Myrtle Beach, South Carolina at U.S. Route 17 Business. It passes through the states of Virginia, North Carolina and South Carolina. From Durham to Laurinburg, a 108-mile (174 km) section of US 501 overlaps U.S. Route 15 (15-501 Concurrency). Sections of US 15-501 also share routings with U.S. Route 1 in sections near Sanford, North Carolina and Aberdeen, North Carolina.

US 501 begins at US 17 Bus. in Myrtle Beach, South Carolina. From Myrtle Beach to Marion, US 501 is a multilane highway and a Freeway with an interchange of US 17 Bypass. It passes through the city of Conway before reaching Marion, where US 501 bypasses the town to the east. North of Marion, US 501 meets SC 38, a connector to Interstate 95. From SC 38, US 501 heads to the northeast, meeting US 301 in Latta. US 301 merges with US 501, forming a concurrency through Dillon to the North Carolina border, where it passes South of the Border prior to exiting South Carolina and an interchange on Interstate 95 near Hamer in Dillon County.

US 301 and US 501 enter North Carolina south of Rowland. In Rowland, US 501 splits from US 301 and heads northwest to Laurinburg, where it briefly overlaps with US 74 south of the city. Upon departing US 74, US 501 immediately embarks on an overlap with US 15. The routes remain concurrent for 108 miles (174 km) to Durham, passing through Aberdeen, Pinehurst, Sanford, and Chapel Hill in between. North of Durham, US 501 passes through the city of Roxboro prior to entering Virginia.

In Virginia, US 501 runs 111.42 miles (179.31 km) from the North Carolina state line near Cluster Springs to its northern terminus at US 60 in Buena Vista. US 501 is the primary highway between Lynchburg and both South Boston in Southside Virginia and Durham in North Carolina's Research Triangle.