The rest of the highway travels straight through rural forestland until it approaches the Waccamaw River Memorial Bridge (Main Street Bridge) over the Waccamaw River.

After crossing the bridge, it enters the Conway Downtown Historic District.

One block later, the highway intersects SC 905 and unsigned US 378 Truck/US 701 Truck at 4th Avenue.

Before the highway enters the city, it is named South Main Street.

However, the highway doesn't officially enter the city limits until just south of the Silver Trace Apartment complex, but the surroundings remain mostly residential, although a few commercial properties can be found further to the north.

Established in 1960 as a renumbering of mainline US 501, along University Drive and Roxboro Street, through downtown Durham.

It begins at the intersection of US 58/360 and heads east overlapping those routes until the US 58/360 overlap ends, then turns onto US 360 until it reaches Hamilton Boulevard, heading northwest until finally reaching its parent route.

The business routes meet the northern end of SR 128 (Mayflower Drive) and cross over Norfolk Southern Railway's Blue Ridge District.

The business routes and US 221 pass through a commercial area and by the Anne Spencer House, then turn west onto 12th Street and cross Norfolk Southern's Danville District rail line a few blocks south of the Lynchburg-Kemper Street Station, which is served by Amtrak.

The business route intersects SR 163 (Memorial Avenue) at the historic home Centerview.

West of Holy Cross Regional Catholic School, US 501 Business leaves the densely populated part of Lynchburg and curves north, passing under a former railroad bridge.

The highway runs 0.99 miles (1.59 km) between junctions with US 501 within the city of Buena Vista.

Just south of the Southern Virginia University campus, the business route veers northwest on Park Avenue, which the highway follows to its northern terminus at US 501 (Beech Street) just south of US 501's northern terminus at US 60.

[8][13][15] Established in 1960 as a renumbering of US 501A along Columbia and Franklin Streets, in concurrency with US 15 Business.