U.S. Route 21 Business (US 21 Bus) traverses through downtown Jonesville and Elkin, via Main Street and Bridge Street. The route was established after the mainline was realigned east along a completed section of I-77.
U.S. Route 21 Business (US 21 Bus) originally traversed along Broughton Street (in concurrency with US 178 Bus), Park Street, and Columbia Road. In 1967, the business loop was decommissioned after the establishment of the second business loop through Orangeburg; the old alignment continues as US 178 Bus (Broughton Street) and US 21 Conn (Park Street and Columbia Street).
U.S. Route 21 Business (US 21 Bus) originally traversed along Main Street, Albright Road, Black Street, Oakland Avenue, and Cherry Road, through downtown Rock Hill. It was decommissioned at the request of Rock Hill to gain ownership and maintenance oversight from the state.