Oklahoma led much of Friday's game, but the third-ranked Sooners couldn't hold on, as Arizona exploded for six runs in the sixth to knock off OU 11-6 in Tucson, Arizona.
The Wildcats' big second inning came with the help of a pair of illegal pitch calls against OU reliever Miali Guachino, then Tayler Biehl delivered a grand slam.
The loss was the Sooners' earliest in a season since they dropped the 2017 season opener. OU hadn't lost before the sixth game since.
In the seventh, Gabbie Garcia led off with a single but Arizona quickly got out of the inning to finish off the comeback victory.
The Sooners lost despite belting four home runs, all in the first two innings.
Oklahoma coach Patty Gasso said her team would have plenty of pop offensively.
In Thursday's 2-1, season-opening win over Arizona State, offense was hard to come by.
The Sooners managed just four hits, with freshman Kendall Wells delivering a two-run, sixth-inning homer to lift OU to the win.
Friday, there was no such slow start.
With two outs in the first, Nelly McEnroe-Marinas belted a two-run, opposite-field home to right to get the scoring started.
Kasidi Pickering followed with another opposite-field homer, this one to left, off Jenae Berry.
The Wildcats got two of the runs back in the bottom half, scratching out the first run thanks to a single, walk and an RBI groundout off Allyssa Parker to start the inning, and then adding another on a passed ball.
Gabbie Garcia led off the second with a homer to center off Berry, driving the Arizona starter from the game, before Parker followed with her first collegiate home run off Jalen Adams.
With two outs and one on in the second, Kierston Deal briefly replaced Parker.
Sereniti Trice delivered an RBI single off Deal to make it 5-3 before Parker reentered to get out of the inning.
The Sooners extended their led once again in the fourth, with Pickering delivering a one-out single to center to score Ella Parker from second.
Arizona cut the OU lead to one in the fifth on Grace Jenkins' two-run, one-out home run to right off Allyssa Parker.
Jenkins' homer drove Parker from the circle, bringing on Sydney Berzon to make her Sooners' debut after transferring from LSU in the offseason.
OU threatened in the sixth, putting two on with one out.
Kai Minor hit a hard liner that looked destined for left field but Biehl, the Wildcats' shortstop, was able to snag the liner.
Sydney Barker then worked a long at-bat against Adams but popped out to second on the 13th pitch of the at bat.
In the bottom half, Arizona put two on with one out thanks to a walk and an error then after a fielder's choice, loaded the bases on Trice's walk.
Gasso then brought in Guachino, who earned the save in Thursday's season opener, to escape the jam.
But Guachino fell behind 2-0, was called for an illegal pitch to make the count 3-0 and then missed the zone with the next pitch to force in the game-tying run.
Guachino was called for another illegal pitch as Jenkins fouled off a 3-1 pitch, forcing in yet another run.
Biehl then followed with a grand slam to center to put Arizona up 11-6.
The Sooners continue their three-game series against the Wildcats at 6 p.m. Saturday before wrapping up the series Sunday.
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