Gary Schofield threw a 12-yard touchdown pass to David Richmond with 3:06 left to win for the visiting Deacons.
Schofield, who sat out last week's victory over Appalachian State with an injury, completed 26 of 44 passes for 271 yards, 206 in the second half. Cyrus Lawrence, VPI's leading rusher, injured his knee in the second quarter. He is expected to be able to play next week.
On their final possession, the Hokies (2-2) drove from their 16 to Wake's 22. After two quarterback sacks totaling losses of 27 yards, Don Wade tried a 65-yard field goal, but it was blocked.
"The game went as we tried to design it," said Coach Al Groh of Wake Forest (3-2). "We told the team earlier in the week that the game probably would be decided in the final four minutes, and probably the final play of the game."
VPI Coach Bill Dooley had a ready reason for the loss: "I think I would say we were consistent in hurting ourselves. It just wasn't an occasional thing. I've never seen so many penalties. We had everything in the book."
VPI was penalized 13 times for 85 yards.