N.C. 751 is a route formed early during the creation of the North Carolina route system. The original system established primary routes with two digit numbers and spurs with an extra digit at the end. NC 751 then was the first spur off of NC 75 which ran along the basic route of today's US 15 and was supplanted by it, and then also by US 501 in the late 1920s. NC 751's first routing took it from NC 75 (Old Chapel Hill Road in Durham) to NC 10, which is now US 70. In the 1950s with US 15-501 put onto a new route to the north, NC 751 was extended along Chapel Hill Street (now University Drive) and south along Hope Valley Road to NC 54. Later it was extended further south to US 64.
North Carolina Highway 751 Truck (NC 751 Truck) is a bypass route for truck drivers that are traveling through the city of Durham. It travels along US 15 Bus/US 501 Bus (Durham-Chapel Hill Boulevard) and US 15/US 501. Signage along the route only appears at key intersections.