The Cougars (2-0) gave second-year coach Kevin Sumlin his first marquee win with the program's first victory over a Top 5 team since an upset of third-ranked Texas in 1984.
Oklahoma State (1-1) was coming off of perhaps the biggest opening win in the program's history last week against Georgia and vaulted into the Top 5 for the first time since 1985. But after overcoming a 17-point halftime lead, the Cowboys squandered their final chances for a win.
Zac Robinson fumbled a snap to end one OSU drive in the fourth quarter, and Jamal Robinson then returned his interception 32 yards for a score to seal the upset with 3:14 remaining.
Dez Bryant returned a punt for a touchdown against Houston for the second straight year as Oklahoma State reeled off 21 straight third-quarter points to surge ahead 28-21. But, unlike last year, Keenum and the Cougars had an answer this time.
And Oklahoma State ran out of weapons. Kendall Hunter, last year's Big 12 rushing leader, didn't play in the second half due to an apparent leg injury and Bryant also missed time. He lay sprawled out on the turf for a few moments after tipping the pass that led to Jamal Robinson's return, and trainers stretched out his right leg before he left the field.
The Biletnikoff Award finalist also didn't return for Oklahoma State's last-ditch drive in the final minutes.
Tyron Carrier caught seven passes for 111 yards and a touchdown, and Beall had 78 yards on 18 carries. He had a 1-yard TD plunge on a fourth down with 13:40 to play that put Houston up 31-28 and provided an answer to Oklahoma State's scoring surge.
Josh Cooper put OSU up one last time with a 22-yard TD catch with 11:22 left, but Keenum led the nation's No. 2 offense from last season right back down the field.
That's when one in a series of fortunate bounces fell the way of the Cougars.
Linebacker Donald Booker leaped to deflect Keenum's pass up in the air, and Beall was able to track it down for the go-ahead score. OSU's chance to respond ended quickly as Bryant tipped the ball into the arms of Jamal Robinson for the pick.
Houston also got a break late in the first half when Matt Hogan's line-drive kickoff smacked off Taylor Sokolosky and was covered up by the Cougars' Tim Monroe. Houston capitalized when Carrier, who's also a sprinter on the track team, took a screen pass from Keenum and raced in for a 32-yard score to make it 24-7 at halftime.