Kole Calhoun hit a leadoff homer and rookie Jaime Barria (7-7) pitched five-hit ball into the sixth inning for the Angels. Los Angeles was in a 1-6 skid before getting back to .500 in this series with the struggling Tigers, who scored only eight runs on an 0-6 California road trip.
Upton connected on a full-count changeup from Blaine Hardy (4-4) for a two-run homer in the fifth shortly before Pujols added his 632nd career homer.
Hardy yielded seven hits over five innings for the Tigers, who are headed home without a win on the West Coast. Detroit has lost 21 of its past 26 road games overall.
The Tigers were shut out for the third time on their road trip. All but three of their eight runs in 58 innings of play out West came in Tuesday night's 11-5 loss to the Angels.
Mike Trout missed his seventh consecutive game with a sore right wrist, but the Angels are hopeful their two-time AL MVP can return against the Oakland Athletics this weekend. Trout had a cortisone shot Monday in his wrist, which has kept him out for the second-longest injury absence of his big-league career.
Barria had another effective outing for the Angels, who have benefited greatly from his surprising emergence as a dependable starter in their injury-plagued rotation. He struck out five and walked one before leaving with two outs in the sixth.
The Angels bullpen then got 10 consecutive outs to finish off Los Angeles' first series sweep since early June.
After Barria struck out three Tigers in the first inning, Calhoun led off for the Angels with his 15th homer. The blast was the ninth leadoff homer in the career off Calhoun, who endured a miserable first half of the season before finding his stride since coming off the disabled list June 18. He has hit 14 homers since that DL stint, tops in the AL during that stretch.
Jefry Marte had an RBI single in the first inning, and he doubled and scored on Jose Briceno's single in the sixth.
Shohei Ohtani had the day off after homering Tuesday night as the Angels' designated hitter.
UNHAPPIEST PLACE ON EARTH
The Tigers haven't won a series at Angel Stadium since August 2009, and they've lost 24 of their past 31 games in Anaheim. They've also lost 31 of their 43 meetings overall with the Angels since September 2012.
Tigers: Catcher John Hicks went on the 10-day disabled list with a right groin strain. The move was retroactive to Tuesday. Detroit recalled catcher Grayson Greiner from Triple-A Toledo to back up James McCann.
Angels: Manager Mike Scioscia is still hoping Tyler Skaggs can start Saturday against Oakland after coming off the 10-day disabled list. Skaggs went on the DL last weekend with a left adductor strain, but the move was retroactive to his previous start.
Tigers: After a day off, Jordan Zimmerman (4-4, 4.31 ERA) makes his 16th start of the season in the opener of a home series against Minnesota.
Angels: After a day off, converted reliever Felix Pena (1-3, 4.97 ERA) makes his ninth start of the season Friday at home against Oakland. Pena has been a solid stopgap for the Halos' troubled rotation. He took a no-hitter into the sixth inning in Cleveland last weekend, but still took the loss.