The loss caps the Sooners' season at 11-3.
WVU rushed for 349 yards and never trailed in a game in which the Mountaineers were heavy underdogs.
Oklahoma trailed 20-6 at halftime, but managed to pull within 20-15 with 6:23 left in the third quarter.
However, a gamble by Bob Stoops backfired and the Sooners never recovered.
Oklahoma attempted a surprise onside kick, but the ball didn't travel the mandatory 10 yards. With great field position, WVU scored in less than three minutes then added another TD by the end of the quarter to push its lead to 34-15.
Twice in the fourth quarter, Oklahoma pulled within 13 points, but both times the Mountaineers took less than a minute to answer with a touchdown of their own.
On a 4th-and-1 play, OU quarterback Sam Bradford hit Quentin Chaney for a 19-yard touchdown with 13:21 left in the game, pulling the Sooners within 34-21. WVU needed just 19 seconds to respond, however, as QB Pat White hit Tito Gonzales for a 79-yard touchdown on its first play.
The Sooners marched down the field in five plays to get within 41-28 on Bradford's 15-yard TD pass to Juaquin Iglesias with 10:20 remaining, but the momentum was again short-lived.
Two plays later, Noel Devine found the outside corner and raced 65 yards for another Mountaineer TD, this one sealing the win.
Whether the loss of three defensive starters was a factor or not, Oklahoma had trouble slowing down any portion of WVU's option rushing attack.
White led the Mountaineers with 150 yards on 20 attempts. Devine picked up 105 on just 12 carries.
Fullback Owen Schmitt had 64 yards on three carries, including a 57-yard scoring romp midway through the second quarter to give WVU a 13-3 lead.
All that running, whether inside or outside, set up White to be effective in his passing. He finished 10-of-19 for 176 yards and two scores.
As good as the WVU offense was - and it was 525 yards good - the defense may have been better.
The Sooners did rack up 421 total yards, but had only six points at halftime and never truly got rolling.
Bradford was 22-of-34 for 245 yards, two TDs and an interception, but it also took him a while to figure out the Mountaineers' defense, which blitzed him from all angles.
The Sooners racked up 176 rushing yards on 43 carries, but never seemed to establish the run game. Allen Patrick led the team with 81 yards on 14 attempts.
The lone bright spots were Quentin Chaney and the kickoff return team.
Chaney, a seldom-used junior wideout thrust into action due to Malcolm Kelly's apparent hamstring injury, had a career night with four catches for 129 yards and a TD. He entered the game with four catches for 56 yards on the season.
The return team, which unfortunately for the Sooners was used nine times, totaled 283 yards. Iglesias led the way with 194 yards on his seven returns. Allen Patrick ran one back 73 yards on his lone attempt.
The kickoff returns constantly gave OU good field position, but the Sooners found it tough to capitalize. One reason was penalties as OU was flagged 13 times for 115 yards.
Oklahoma couldn't muster a point in the first quarter as WVU put up a 6-0 lead on a pair of Pat McAfee field goals.
Garrett Hartley put the Sooners on the scoreboard with a 37-yard field goal with 7:43 to go in the first half.
That's when Schmitt broke free for the longest WVU TD run in its bowl history – a record that was short-lived.
Hartley's 24-yard field goal at 4:50 of the second quarter had Oklahoma within 13-6, but the defense again broke down as WVU drove 78 yards in seven plays to go up 20-6. The drive ended on White's 21-yard TD pass to a wide open Darius Reynaud.
The Sooners showed a sense of urgency early in the second half, but penalties held them to a 42-yard Hartley field goal on their first drive. Oklahoma then managed a seven-play, 80-yard drive to pull within 20-15 on Chris Brown's one-yard plunge at 6:23, which set up the surprise onside kick.
Oklahoma's loss was its fourth straight in a BCS game. The Sooners lost the BCS title games in 2003 (LSU in the Sugar) and 2004 (USC in the Rose) and was defeated by Boise State in last year's Fiesta Bowl.