In Virginia, US 221 runs 149.61 miles (240.77 km) from the North Carolina state line near Independence north to its northern terminus at US 29 Business, US 460 Business, and US 501 Business in Lynchburg.
 US 221 connects Independence, Galax, and Hillsville in Southwest Virginia while running concurrently with US 58.
 The U.S. Highway connects those communities with Roanoke via Floyd County, within which US 221 is the main west–east highway.
The U.S. Highway also runs concurrently with US 460 from Roanoke to Bedford and parallels that U.S. Highway from Bedford to Lynchburg.
In Virginia, US 221 runs 149.61 miles (240.77 km) from the North Carolina state line near Independence north to its northern terminus at US 29 Business, US 460 Business, and US 501 Business in Lynchburg.  US 221 connects Independence, Galax, and Hillsville in Southwest Virginia while running concurrently with US 58.  The U.S. Highway connects those communities with Roanoke via Floyd County, within which US 221 is the main west–east highway. The U.S. Highway also runs concurrently with US 460 from Roanoke to Bedford and parallels that U.S. Highway from Bedford to Lynchburg.
U.S. Route 221