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highway, US 21 only travels through three states and is no longer a cross-country route, as many sections have been replaced by I-77 in Ohio and West Virginia.

US 21 originally ran from Cleveland, Ohio, to Yemassee, South Carolina, it was later extended to Beaufort and Hunting Island State Park.

Beginning at Hunting Island State Park, US 21 travels west toward Beaufort, where it widens to four lanes.

The route bypasses Beaufort to the south, going through Port Royal, Shell Point, and Burton.

The route travels in a wrong-way concurrency with US 17 south for seven miles (11 km) before turning north toward Yemassee, where it becomes a rural two-lane road and intersects with US 17 Alternate.

In York County, US 21 enters urban areas again, connecting Rock Hill and Fort Mill.

Its first break with I-77 is along Statesville Avenue, then proceeding through Huntersville and Cornelius, however, because of its close proximity to I-77 and North Carolina Highway 115 (NC 115), it has no interchange with I-485 by itself.

After a few miles crossing the state line, US 21 reaches the town of Independence, where it splits with US 221 and continues north.

The route goes through the Mount Rogers National Recreation Area before entering the city of Wytheville.

US 21 in the pre-Interstate era was a north–south highway connecting the area around Lake Erie and the coastal South.

One of the few true north–south routes to cross the middle Appalachian Mountains, it became an important corridor for motor traffic between northeastern Ohio, western Pennsylvania, (with US 19) and western New York with central North Carolina, central and southeastern South Carolina, and (by connecting with other highways) coastal Georgia and most of Florida.