U.S. Route 501 is a north–south United States highway that traverses the majority of North Carolina in concurrency with U.S. Route 15, known as the "15-501" ("Fifteen Five-o-one").

US 501 enters North Carolina at the South Carolina state line with an intersection of I-95 while overlapping US 301, nearby South of the Border. It goes northwest, through Rowland where the overlap with US 301 terminates, and Raemon, to Laurinburg. Once at Laurinburg, it overlaps briefly with I-74/US 74 before connecting with US 15. The majority of the route, to this point, is two-lane rural road.

Merging with US 15, it becomes what is known as the "15-501" ("Fifteen Five-o-one"), a concurrency that extends for 106 miles (171 km) across central North Carolina. After Laurinburg it goes north to Aberdeen, linking briefly with US 1 before continuing to Pinehurst. In Pinehurst, 15-501 goes through a rare roundabout, then continues north, through Carthage, back to US 1. After another brief concurrency with US 1 through Sanford, it exits off the freeway and goes due north to Pittsboro. After Pittsboro, 15-501 becomes an expressway, connecting the cities of Chapel Hill and Durham; this section of the route is famous because of the two universities it connects: University of North Carolina at Chapel Hill and Duke University. Though the road is a symbol of the separation of the Carolina-Duke rivalry, NCDOT has been trying to remedy that by making the route a superstreet for better traffic flow. In Durham, 15-501 upgrades to an urban freeway, allowing for quick access from south Durham to north; the freeway ends merging into Interstate 85. At exit 176B (on I-85), US 501 splits off towards Roxboro, while US 15 continues with I-85 towards Oxford.

After Durham, US 501 goes north to Roxboro, then onto South Boston, Virginia; the majority of which is a four-lane expressway.

Established in 1927, it was aligned along NC 13 from Durham north, through Roxboro, to the Virginia state line.

In 1934, it was overlapped with US 15 from Durham south to Laurinburg. From there, it went southeast to Rowland and then to the South Carolina border. This extension south replaced NC 22, NC 71, and NC 241.

In 1953, US 501 was bypassed around Chapel Hill. In 1956 or 1957, US 501 was bypassed west of Sanford. Between 1960-1962, US 501 was bypassed around Laurinburg.

Established in 1960 when mainline US 501 was bypassed around Laurinburg. US 501 Business, in concurrency partly with US 15 Business and US 401 Business, traverses along Jones Road, Main Street, and Aberdeen Road.

The entire route is in Laurinburg, Scotland County.

Established in 1957 when mainline US 501 was bypassed west of Sanford. US 501A, in concurrency with US 1A and US 15A, traversed on Carthage Street and Hawkins Avenue. In 1960, it was renumbered as US 501 Business.

Established in 1960 as a renumbering of US 501A along Carthage Street and Hawkins Avenue, in concurrency with US 1 Business and US 15 Business. Between 1976-1978, US 1 Business was rerouted along NC 42 on Wicker Street; it is believed that both US 15 Business and US 501 Business were decommissioned by that time.

Established in 1953 when mainline US 501 was bypassed around Chapel Hill. US 501A, in concurrency with US 15A, traversed on Columbia Street and Franklin Street. In 1960, it was renumbered as US 501 Business.

Established in 1960 as a renumbering of US 501A along Columbia and Franklin Streets, in concurrency with US 15 Business. It was decommissioned between 1985-1987.

Established in 1960 as a renumbering of mainline US 501, along University Drive and Roxboro Street, through downtown Durham. It is in concurrency with US 15 Business for majority of its route and has relativity unchanged since inception.

The entire route is in Durham, Durham County.