U.S. Route 21 or U.S. Highway 21 (US 21) is a major north–south United States Numbered Highway in the Southeastern United States that extends 394 miles (634 km). The southern terminus is in Hunting Island State Park, South Carolina, 14.4 miles (23.2 km) south of the junction with US 21 Business and South Carolina Highway 802 (SC 802) in Beaufort. The northern terminus is in Wytheville, Virginia, at an interchange with Interstate 81 (I-81) and US 52. Despite the "1" indicating that it is a major north–south highway, US 21 only travels through three states and is no longer a cross-country route as it has been replaced with I-77 in both Ohio and West Virginia. It also has the second-shortest length of all of the major north–south routes, just behind US 91. The route travels through the states of South Carolina, North Carolina, and Virginia. It also connects through major Southeastern cities such as Columbia, South Carolina, and Charlotte, North Carolina. The northern portion of the road travels parallel to I-77 in northern South Carolina and North Carolina. The road also has three interchanges with I-26 in Lexington and Calhoun counties in South Carolina.

The United States Numbered Highway System is an integrated network of roads and highways numbered within a nationwide grid in the contiguous United States. As the designation and numbering of these highways were coordinated among the states, they are sometimes called Federal Highways, but the roadways were built and have always been maintained by state or local governments since their initial designation in 1926.