Pujols hit his 35th home run of the season and 555th of his career, moving into a tie for 14th with Manny Ramirez on baseball's all-time list. He also became the fourth player in major league history to hit 35 homers or more at least 10 times in their first 15 seasons, joining Willie Mays, Mike Schmidt and Alex Rodriguez.
Pujols lined a two-run shot in the second inning off A's ace Sonny Gray (12-7), reaching the 35-homer mark for the first time since hitting 37 in 2011, his final season with St. Louis. Pujols went 2-for-5, drove in three runs and scored twice.
"Manny is probably one of the best right-handed hitters who ever played the game," Pujols said. "To be in the same page with him and, along the way, with so many great hitters I passed this year is awesome."
Angels rookie left-hander Andrew Heaney (6-2) allowed three runs on seven hits over seven innings. He gave up all three runs in the first inning and blanked the A's in the next six, posting his first victory since July 26 against Texas. He struck out six and walked none.
The Angels (67-66) won their second straight game and took two of three games in the series. They went 4-5 on a nine-game road trip.
Gray lost his third straight game. He gave up a season-high six earned runs and lasted only five innings, matching his season low.
"I didn't think all the pitches I made were that bad, but they put some good swings on the ball and had four runs before you knew it," Gray said.
Gray gave up eight hits, walked one and struck out two, equaling another season low. He allowed four runs in the first inning and two in the second, falling to 5-2 for his career against the Angels.
"We beat a tough pitcher," Pujols said. "He has our number. We were able to get to him today early and make him throw a lot of pitches. I think that was the best probably over the last three years that we hit against Sonny Gray."
Left fielder David Murphy went 3-for-4 with an RBI and scored a run for the Angels. Right fielder Kole Calhoun had three hits in four at-bats, walked once and scored twice.
Third baseman David Freese went 2-for-4, and center fielder Mike Trout was 2-for-5 with a double and scored a run.
Catcher Josh Phegley hit a two-run homer for the A's, his eighth home run of the season. Second baseman Brett Lawrie went 2-for-4 with his career-high 15th home run and a double. Designated hitter Billy Butler had two hits, including his 300th career double and No. 24 this season.
The Angels sent eight batters to the plate in the first inning, forcing Gray to throw 26 pitches.
Calhoun lined a leadoff single off first baseman Mark Canha's glove and moved to third on Trout's single to center. Calhoun scored on a wild pitch and Pujols moved Trout to third with a wicked single that shortstop Marcus Semien got his glove on -- directly in front of his face -- but couldn't catch as he fell backward.
"I swear I closed my eyes because I thought that ball hit him in the head," Pujols said. "That's probably one of the hardest balls I've hit this year."
Murphy grounded an RBI single to right, driving in Trout. First baseman C.J. Cron brought Pujols home with a groundout to make it 3-0. Freese made it 4-0 with a run-scoring single to right.
Lawrie lined a one-out double in the bottom of the first and scored on third baseman Danny Valencia's single. Phegley cut the Angels' lead to 4-3 with a two-run homer to center.
"I was up in the zone, I was flat, I was falling behind," Heaney said. "I didn't make good pitches when I was behind in the count. It's really nice the way the offense is going right now to put up four that I almost (threw) away. ... I was just trying to settle in."
The Angels extended their lead to 6-3 in the second when Calhoun walked and Pujols lined Gray's 0-2 pitch over the left-field wall.
"I went and looked at it and Phegley was going down to block it," Gray said of the pitch. "Pujols just kind of stayed down and was able to backspin it. Just shows how strong he is."
NOTES: Oakland RHP Evan Scribner suffered a torn right lat Monday night in the ninth inning against the Angels and won't pitch again this season, manager Bob Melvin said. Scribner tore the same muscle in July 2011 while with San Diego and missed the rest of that season. The reliever is not expected to have surgery and should be ready for spring training, Melvin said. ... A's RHP Cody Martin was optioned to Triple-A Nashville, one day after making his A's debut and first major league start. Martin gave up five runs on six hits in three innings in a 6-2 loss to the Angels. ... Angels 1B/LF Efren Navarro was recalled from Triple-A Salt Lake. ... The Angels are off Thursday before opening a three-game series Friday against Texas, which owns the American League's second wild-card spot, but manager Mike Scioscia said he won't adjust his rotation for the series. "We have a lot of guys that can really use the extra day off," he said.