Breece Hall scored the go-ahead touchdown on an 8-yard run with 4:06 left and Isheem Young intercepted Spencer Rattler in the end zone on No. 18 Oklahoma's final drive, giving Iowa State a 37-30 win Saturday night.
It was the Cyclones' first win over OU in Ames since 1960.
The Sooners (1-2, 0-2 Big 12), beaten at home by Kansas State last week, lost back-to-back regular-season games for the first time since 1999 and likely had their hopes for a fourth straight College Football Playoff appearance dashed.
The Cyclones (2-1, 2-0) wore down the Sooners with the running of Hall, who rushed for 139 yards. Iowa State's Brock Purdy passed for 254 yards and ran for a 2-yard touchdown to tie it 30-all.
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Isaiah Thomas seemed to turn momentum in the Sooners' favor when he sacked Purdy, causing him to fumble at the Cyclones' 39. Four plays later Rattler found Jeremiah Hall for a 4-yard touchdown pass that put Oklahoma up 30-23 with 8:17 left.
Kene Nwangwu returned the ensuing kick off 85 yards, setting up Purdy's short touchdown run to tie the game.
Rattler had played a strong game, committing no turnovers before Young stepped in front of his pass to Charleston Rambo to secure one of Iowa State coach Matt Campbell's biggest wins in five years in Ames.
Oklahoma: Defense is still a problem. A week after failing to protect a 21-point, third-quarter lead against Kansas State, the Sooners were gashed by the Cyclones. A prime example came in Saturday's third quarter. After a defensive holding penalty extended an Iowa State drive, Oklahoma gave up a 65-yard touchdown pass and the Cyclones owned a 23-20 lead.
Iowa State: Purdy was not rattled and hit 12 of 24 passes for 254 yards and the defense came up big when it had to.
Sophomore kicker Gabe Brkic's school-record streak of 18 consecutive made field goals ended just before halftime when his 54-yard try sailed wide right as time expired. Brkic was the only FBS kicker to make all his field goals and point-after attempts in 2019, going 17 for 17 and 52 for 52. He made a 51-yarder early in the fourth quarter to even the score at 23-23.
The No. 18 Sooners began the season as a playoff contender and were No. 3 before losing to Kansas State. They likely will fall out of the Top 25.
Oklahoma vs. Texas (at Dallas) Saturday.
Iowa State hosts Texas Tech on Saturday.