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.
Ray Liotta sues skin care company over use of likeness
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