U.S. Route 421 Business (US 421 Bus) was established in November 1969 as a renumbering of all US 421A and part of mainline US 421.

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.

[9][10] U.S. Route 421 Business (US 421 Bus) was established by 1970 as a renumbering of mainline US 421 along Third Street to the Isabel Holmes Bridge.

[12][unreliable source] U.S. Route 421 Alternate (US 421A), was established by 1952 when mainline US 421 was bypassed west.