U.S. Route 421 Business was established on November, 1969 as a renumbering of all US 421A and part of mainline US 421. The 6.2 miles (10.0 km) route begins along Statesville Avenue heading into downtown North Wilkesboro, where it follows along Main Street, 6th Street, and D Street. It reconnects with mainline US 421 in Wilkesboro.
U.S. Route 421 Truck, is an alternate route for trucks in Boone, which are not allowed to go through the downtown area. The route starts south on NC 105 from US 421 Kings Street to NC Highway 105 Bypass, then back to US 421 west of Boone. US 221 Truck and US 321 Truck also overlap along the route.
U.S. Route 421 Business (US 421 Business) is a business route of US 421 in Scott County. The business route is co-existent with US 23 Business and US 58 Business through Gate City. US 421 Business begins at the east end of the town at an intersection with US 421, US 23 and US 58. The business route heads west along Kane Street, which crosses Norfolk Southern Railway's Appalachia Division rail line on its way to the downtown area, where the route meets the southern end of SR 71 (Jackson Street). US 421 Business turns west onto Jackson Street and parallels the rail line to the business route's western end at an interchange with US 421, US 23, and US 58 just west of the western town limit of Gate City.
U.S. Route 421 Alternate (US 421A), was established by 1952 when mainline US 421 was bypassed west. It followed Lisbon Street and McKay Streets, with a partial overlap with US 701A. In 1960, the route was renumbered as US 421 Business.
U.S. Route 421 Alternate (US 421A), was established in 1957 when mainline US 421 was bypassed south through Wilkesboro; the old alignmet continued to go through downtown North Wilkesboro via D Street. On November, 1969, it was renumbered as part of US 421 Business.