US 15 enters Mecklenburg County, Virginia at the North Carolina state line several miles south of Clarksville. The U.S. Highway continues south toward Oxford and the Research Triangle. US 15 heads north as two-lane National Highway, which parallels the Virginia Southern Railroad north across the Grassy Creek branch of Kerr Lake. The U.S. Highway expands to a four-lane divided highway in an industrial area adjacent to Marks Municipal Airport. US 15 passes through a partial cloverleaf interchange with the US 58 bypass, then becomes an undivided highway on entering the town of Clarksville as College Street and crossing over the rail line. The U.S. Highway turns east onto Virginia Avenue, which also carries US 58 Business and SR 49.