Rod Rutherford threw three touchdown to Larry Fitzgerald for the Panthers (7-2, 4-0 Big East), who suddenly find themselves in contention for the conference title with Miami.
The Hokies (8-1, 3-1) were out to avenge a humbling 38-7 loss to Pittsburgh at Heinz Field last season and appeared to be on their way after taking an early 14-0 lead.
But the Panthers regrouped and finally took their only lead of the game when Miree bounced off safety Willie Pile and rumbled down the middle of the field and into the end zone.
Miree, who carried 23 times for 161 yards, dealt a devastating blow to the national title hopes of the Hokies, who were sixth in the latest BCS poll but had a chance to make up ground since they face top-ranked Miami on Dec. 7.
Instead, Virginia Tech was left wondering what might have been. Rutherford completed just 11 of 26 passes for 203 yards, but Fitzgerald caught five of the passes for 105 yards.
Pittsburgh overcame a big game from Lee Suggs, who carried 25 times for 128 yards and a score. Virginia Tech, however, played most of the game without its other star running back, Kevin Jones, who left in the first quarter with a pulled left hamstring.
Strong special teams, a staple at Virginia Tech under Coach Frank Beamer, enabled the Hokies to jump to an early two-touchdown lead.
Andy Lee's punt was blocked and Jimmy Williams returned the ball 20 yards to the Pittsburgh three, setting up a three-yard touchdown run by Jones.
Lee later had trouble with a snap and was tackled short of a first down at the Pittsburgh 21. Following a pass interference penalty, Suggs scored on a one-yard run, giving the Hokies a 14-0 bulge.
Pittsburgh responded on its next possession as Rutherford lofted a 31-yard touchdown pass to Fitzgerald, cutting the halftime deficit to 14-7.
Virginia Tech appeared to take control early in the third quarter when Suggs went around left end and raced 58 yards for a touchdown to increase the lead to 21-7.
Pittsburgh refused to lose its composure. Following a personal foul on Virginia Tech, Rutherford completed a 45-yard pass to Kris Wilson and followed with a 14-yard touchdown pass to Fitzgerald in the corner of the end zone.
The momentum stayed Pittsburgh's way when Vinnie Burns returned a punt 56 yards and Rutherford again found Fitzgerald, this time with a perfectly thrown 10-yarder over the receiver's shoulder that tied the score at 21-21.
Pittsburgh had a chance to take the lead later in the quarter when it drove to the Virginia Tech five before DeAngelo Hall picked off an errant pass from Rutherford and returned it to midfield.