From there, it continues north, crosses I-20, and goes through the cities of Bishopville and Hartsville to the town of Society Hill.

Past Pittsboro, US 15/US 501 goes toward Chapel Hill and skirts around the southeastern edge of the city and then across I-40 to Durham.

It then crosses back over I-85, goes through the city of Oxford, on through Bullock, and then to the North Carolina–Virginia state line.

The highway goes through the town of Clarksville and merges very briefly with US 58/State Route 49 (SR 49) and then crosses over the main body of Kerr Lake.

After a brief merge with US 460, US 15 goes through the towns of Dillwyn, New Canton (on the James River), Fork Union, and Palmyra before crossing I-64 at Zion Crossroads.

US 15 starts in Maryland at Point of Rocks, crossing the Potomac River and then merges into US 340 just south of Frederick.

The concurrency ends at Shamokin Dam, where US 11 splits and follows the North Branch Susquehanna River, and US 15 follows the West Branch Susquehanna River north toward Williamsport where it passes through Lewisburg and the campus of Bucknell University (which is partially bisected by the highway).

The segment from Williamsport, Pennsylvania, to the northern terminus at I-86 and NY 17 in Painted Post, New York, has been completely upgraded to Interstate standards, except for one access road at milemarker 150.1, in preparation for the eventual transition to designation as I-99, as has the US 15/I-86 interchange.

The 12.59-mile (20.26 km) segment of US 15 in New York runs parallel to the Tioga River from the state line to its current northern terminus at I-86 and NY 17 exit 44 at the junction of the Tioga and Cohocton rivers in Painted Post, west of downtown Corning.

Prior to the completion of the Tioga Creek flood-control project, hastened by the flooding caused after Hurricane Agnes along the Pennsylvania and New York segments of US 15 in June 1972, US 15 passed through many small towns in Pennsylvania as it passed from Lawrenceville, at the New York border, to West Milton, where the road begins to follow the west bank of the Susquehanna River.

Originally a winding two-lane road over numerous mountains, US 15 now bypasses many small towns such as Sebring, Blossburg, Covington, Canoe Camp, and Hepburnville.

Near Tioga, Pennsylvania, drivers crossing the tall concrete bridge can see where a two-lane road (formerly US 15), still marked with double yellow lines, disappears into the water.

In October 2009, a 180-mile (290 km) portion of US 15 from Charlottesville, Virginia, to Gettysburg, Pennsylvania, was designated a National Scenic Byway by the U.S. secretary of transportation.