The Cowboys saw their hopes for a national title virtually disappear in a result that likely created chaos in the race for spots in the championship game.
Only two unbeaten teams are left in major college football -- No. 1 LSU and No. 10 Houston. Alabama, Oregon, Oklahoma and Arkansas are all in position to make a case for a shot at the national crown.
Oklahoma State owned a 24-7 lead in the third quarter, but Iowa State rallied behind a quarterback playing in only his fifth college game. Jared Barnett completed 30-of-57 passes for 367 yards and three touchdowns, one of which came in overtime.
Barnett's 7-yard scoring throw to Albert Gary with 5:30 left in the fourth period forged a 24-24 tie and Iowa State regained the ball with 4:15 to play.
The Cyclones appeared to have lost a chance at victory, however, when Alex Elkins intercepted a Barnett pass that put Oklahoma State in position to kick a field goal.
Quinn Sharp, however, missed a 37-yard attempt with 1:21 to play and the contest headed for overtime.
Iowa State quickly scored in the first extra on a 25-yard throw from Barnett to James White, but Oklahoma State answered with a 6-yard touchdown toss from Brandon Weeden to Josh Cooper. Weeden finished with 474 passing yards and three touchdowns.
The Cowboys took the ball to start the second overtime and on the first play of the drive Weeden was intercepted by Ter'ran Benton.
Three running plays through a disheartened Oklahoma State defense led to the winning touchdown.
The Cowboys (10-1 for the year and 7-1 in Big 12 Conference play) will have 16 days to prepare for their closing contest against Oklahoma, where they had hoped to finish off a perfect regular season. Those hopes were wiped out by an Iowa State team that is a mere 5-5 on the year and 3-5 in league play.