U.S. Route 221 (US 221) is a part of the U.S. Highway System that runs from Perry, Florida to Lynchburg, Virginia. In Virginia, the U.S. Highway 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 east–west highway. Entering Bedford County, US 221 exits the Blue Ridge Mountains; it then passes through the Piedmont town of Bedford on its way to Lynchburg and shares a brief overlap with US 460 Business through the town. The U.S. Highway also runs concurrently with US 460 from Roanoke to Bedford and parallels that U.S. Highway from Bedford to Lynchburg.

Lynchburg is an independent city in the Commonwealth of Virginia in the United States. First settled in 1757 by ferry owner John Lynch, the city's population was 79,009 at the 2020 census, making Lynchburg the 11th most populous city in Virginia. Located in the foothills of the Blue Ridge Mountains along the banks of the James River, Lynchburg is known as the "City of Seven Hills" or the "Hill City". In the 1860s, Lynchburg was the only city in Virginia that was not recaptured by the Union before the end of the American Civil War.