U.S. Route 220 Business (US 220 Bus) was established in 1966 when mainline US 220 was rerouted onto new freeway bypass from south of Ulah to Vision Drive, in Asheboro.

[4] In 1974, US 220 Bus was removed from Vision Drive and continued north along the old mainline route, through Randleman, to Level Cross.

In 1982, US 220 Bus was adjusted at Level Cross, replacing some of the mainline to its current terminus with US 220 interchange.

U.S. Route 220 Business (US 220 Bus) departs US 220 at the junction with US 58 south of Martinsville in Henry County.

After re-entering Henry County, US 220 Bus intersects Commonwealth Boulevard and changes its name to Virginia Avenue.

[11] In the 1990s, the section from Bonsack to Cloverdale was widened to four lanes and it serves as a bypass for US 460 seeking to avoid Roanoke traffic congestion.

South of the borough, the route winds over the hilly approach to the town at much steeper grades than does the freeway.

After exiting the municipality, it briefly becomes four lanes as it accommodates a variety of travel services at the interchanges with the Turnpike and I-99.

The route begins at Exit 15 of Interstate 99, in the southernmost point of Blair County, Pennsylvania.

Afterward, it becomes Plank Road between Hollidaysburg and Altoona, feature four-lanes, a center turning lane, and a copious commercial development.

As part of the ongoing completion of Interstate 99, U.S. 220 was shifted on to the Mount Nittany Expressway around State College, Pennsylvania.

In 2013, mainline US 220 was moved back onto its original route through Ellerbe, deleting the business loop.