Tight end Dwayne Allen hauled down four passes for 75 yards and a touchdown from Tajh Boyd, who piled up 204 yards on just 13-of-32 passing for Clemson (5-0, 2-0 ACC).
The Tigers got off to their first 5-0 start since 2000 despite the nation's touchdown receptions leader, Sammy Watkins, being held to just 38 yards on three catches.
Mike Bellamy added 47 rushing yards, including a 31-yard TD run in the victory.
Logan Thomas mustered just 125 passing yards on 15-of-27 efficiency for the previously unbeaten Hokies (4-1, 0-1), who lost an ACC opener for the first time since joining the conference in 2003.
David Wilson gained 123 yards on 20 carries in Virginia Tech's loss.