Traveling east–west within the Piedmont Triad, it connects the towns of Rural Hall, Walnut Cove, Stokesdale and Wentworth with the city of Reidsville.

[1] The signed highway begins at exit 118 of US 52 (John M. Gold Freeway) on the border between Winston-Salem and Rural Hall.

Heading northeast out of the town, it travels into a more rural area of Forsyth County before entering Germanton and has a concurrency with NC 8.

After a brief concurrency with US 311, NC 65 has a short segment where it crosses a railroad at-grade and makes a left turn to continue towards Stokesdale.

[2] NC 65 travels northeast, later north-northeast, through a mostly forested area with some clusters of small farms and houses.

Shortly after NC 704, the highway enters the town limits of Wentworth, also the seat of Rockingham County.

The road heads east and southeast through the small town passing county offices and Rockingham Community College and the Carter Plantation.

They pass Rockingham County High School and a quarry until the road reaches an interchange with US 158 and US 29 Bus.

In 1929, NC 65 was adjusted along a more straight route between Winston-Salem and Stokesdale, bypassing south of Belews Creek.