SR 49 begins at the North Carolina state line in the town of Virgilina in southeastern Halifax County.

The two highways cross over the old railroad grade of the Norfolk, Franklin and Danville Railway then intersect Seventh Street.

SR 49 turns east onto Seventh Street, leaving the town and becoming Clarksville Road, which closely parallels the state line for a short distance before veering northeast and entering Mecklenburg County after crossing Aarons Creek, which flows north into the Dan River.

After passing through the downtown area, SR 49 and US 15 leave the town of Clarksville by crossing the John H. Kerr Reservoir, an impoundment of the Roanoke River that is also known as Buggs Island Lake, on the Phillip Saint Julian Wilson Bridge and a causeway.

SR 49 and US 15 turn north, cross over the Virginia Southern rail line, and parallel the eastern shore of the lake until the two highways split at the hamlet of Dortch Store.

The state highway gains the name Courthouse Road, which it carries as it bridges the Middle Meherrin River and North Meherrin River and passes through the county seat of Lunenburg, where SR 40 (Lunenburg County Road) joins the highway in a concurrency northeast to the town of Victoria.

SR 49 crosses Deep Creek before reaching its northern terminus at US 360 (Patrick Henry Highway) northeast of Burkeville.