U.S. Route 321

U.S. Route 321 is a spur of U.S. Route 21. It runs for 526 miles (847 km) from South Carolina to Tennessee. The northern terminus of U.S. 321 is between Lenoir City and Oak Ridge, Tennessee, at Interstate 40 exit 364, which is about 4 miles (6.4 km) west of Interstate 40's junction with Interstate 75. The southern terminus is in Hardeeville, South Carolina at the intersection with U.S. Route 17, less than a mile away from Interstate 95 and 15 miles (24 km) north of Savannah, Georgia.

Because of its unusual "north–south–north" route, U.S. 321 intersects both Interstate 40 and U.S. Route 70 three separate times.