The route enters the state from South Carolina near Calabash and leaves in the vicinity of the Great Dismal Swamp National Wildlife Refuge in Virginia.

US 17 then travels east through the city of Wilmington with US 76 on Wooster/Dawson streets and Oleander Drive, intersecting US 117, North Carolina Highway 132 (NC 132), and US 74.

At the end of the US 76 concurrency near Wrightsville Beach, US 17 travels north as Military Cutoff Road before meeting up with Market Street and US 17 Business (US 17 Bus.)

Between New Bern and James City, US 17 (concurrent with US 70 and NC 55) crosses the Trent River by way of the Freedom Memorial Bridge.

[3] In May 2015, the American Association of State Highway and Transportation Officials (AASHTO) approved a request to reroute US 17 back through Wilmington, following US 76 along Oleander Drive and Military Cutoff Road.

[7] In 2012, the North Carolina Department of Transportation (NCDOT) backed and presented a letter to the Federal Highway Administration (FHWA) requesting the establishment of a new high priority corridor between Raleigh and Norfolk, designated I-44 (or I-50, with I-56 and I-89 as other possible numbers).

[3] In Chowan County, the existing freeway section of US 17, which bypasses Edenton, will be fully upgraded to modern Interstate standards.

At a cost of $13 million, it will mainly focus on widening travel lanes and building shoulders; construction is planned to start in 2025.