Joseph Randle carried the ball 18 times for 78 yards and three touchdowns for the Cowboys (10-0, 7-0 Big 12), who are off to their best start since the school's lone undefeated season in 1945.
Herschel Sims rushed for 109 yards on 13 carries for Oklahoma State, which has won 10 games in two straight seasons for just the second time ever and for the first time since 1987 and 1988.
Justin Blackmon and Josh Stewart each had two receiving touchdowns for the Cowboys, who wrap up the regular season with games against Iowa State and Oklahoma.
Seth Doege connected on 25-of-43 passes for 169 yards and an interception for the Red Raiders (5-5, 2-5), who have lost three in a row for the first time since 1998.
The Cowboys dominated the game from the start. After forcing Texas Tech to go three-and-out, Oklahoma State started its first drive of the contest at the 41. Josh Cooper caught passes of 23 and 13 yards prior to Blackmon catching two-yard fade in the right corner of the end zone.
Oklahoma State was forced to punt on its next possession, but Texas Tech's Alex Torres fumbled the ball. The Cowboys recovered at the 29 of the Red Raiders. Randle caught three straight passes before running into the end zone from two yards out.
The Cowboys added another touchdown late in the first quarter. Weeden completed all five of his passes during an 81-yard march that Stewart capped with a 27-yard score with 1:42 left.
Doege was intercepted by Cooper Bassett on the ensuing Texas Tech drive. The second play of the second period resulted in an Isaiah Anderson 28-yard TD catch for a 28-0 margin.
Things got worse for the Red Raiders on the ensuing kickoff. After picking up his own teammate's fumble near the goal line, Ben McRoy lost the ball himself. McRoy failed to locate the ball and Stewart jumped on the ball in the end zone for an Oklahoma State touchdown.
Randle's one-yard rushing TD with 5 1/2 minutes remaining made it a 42-0 contest. He added a 10-yard score with 37 seconds left to give the Cowboys a 49-0 lead.
Cornelius Douglas put Texas Tech on the board early in the third quarter with a 37-yard fumble return for a touchdown. The two-point conversion failed to keep it 49-6.
Blackmon's 48-yard TD catch with 11 1/2 minutes left made it a 50-point contest. Stewart added a 66-yard TD catch with under four minutes to go for a 63-6 margin.
Quinn Sharp made a 37-yard field goal early in the fourth to make it 66-6.
Texas Tech owns a 21-15-3 lead in the all-time series with Oklahoma State, but the Cowboys have won the last three meetings...Weeden is 21-2 as a starter, including an 11-0 mark away from Boone Pickens Stadium...Texas Tech has lost four in a row at home for the first time since 1990...Oklahoma State surpassed the 50-point mark for the sixth time this year and the 60-point mark for the third time this year. OSU has scored 52 or more points in each of its last three games..At 7-0 in Big 12 play, Oklahoma State set a new school record for conference wins in a season.