Baron Batch ran for 136 yards and two scores for the Red Raiders (7-4, 4-3 Big 12), who became bowl eligible for the 16th straight season.
Oklahoma (6-5, 4-3) has its most losses since going 7-5 in 1999. It was just the fifth victory in 17 meetings for Texas Tech against the Sooners, and the Red Raiders had never won by more than 10 points in the series.
The margin was a stunning reversal from last season, when the Sooners crushed Texas Tech 65-21 to end the Red Raiders ' national championship hopes. Oklahoma hadn't lost this badly since falling to Texas 45-12 in 2005.
Texas Tech's Alex Torres had his best game of the season with 11 catches for 163 yards.
The victory was No. 83 for Mike Leach, surpassing predecessor Spike Dykes as the winningest coach at Texas Tech.
The Sooners' pass defense came in at No. 18 in the nation (178 yards per game) but couldn't hold back Texas Tech's passing offense, ranked second in the country.
Brandon Sharpe helped keep the Oklahoma offense out of rhythm. He entered the game second in the nation in sacks and added 2 1/2 more Saturday.
Landry Jones was 18 of 35 for 262 yards for the Sooners.
With Texas Tech comfortably ahead at the start of the fourth quarter, Red Raiders fans and players began to hop up and down to House of Pain's ''Jump Around,'' reciprocating what Sooners fans did at Memorial Stadium during last November's rout of the Red Raiders.
That loss ended Tech's unbeaten season and kept the Sooners ahead of Texas in the BCS standings, which helped send OU to play for the national championship against Florida.