The state highway runs 34.06 miles (54.81 km) from U.S. Route 23 (US 23), US 58, and US 421 in Clinchport north to US 58 Alternate in Castlewood.

SR 65 begins at an intersection with US 23, US 58, and US 421 (Orby Cantrell Highway) just west of the town limit of Clinchport.

The state highway heads northeast through the town as 2nd Avenue, which passes under CSX's Kingsport Subdivision.

Within the town, SR 72 continues north parallel to the railroad and the Clinch River as Hanging Rock Parkway while SR 65 crosses the river and heads east as Sinking Creek Highway, which follows Sinking Creek across the Scott–Russell county line.

The state highway, now named Mew Road, passes through the hamlet of Mew while passing through a broad valley on its way to its northern terminus at US 58 Alternate (Castlewood Road) at Banners Corner in the unincorporated area of Castlewood.