Guerrero's first homer since July 5, two days before a muscle strain behind his left knee sidelined him for three weeks, was a lift for everyone -- including fellow Dominican Republic native Santana, who climbed off the ropes in the third inning and found smooth sailing into the sixth to move to 4-6.
"It's about time," Santana said, grinning, referring to Guerrero's towering blast to left for his fifth homer of an injury-riddled season and No. 397 of his Hall of Fame-level career.
Held to six runs in the first two games, the Angels had that many before losing pitcher John Danks (9-8) got an out in the third inning.
"It wasn't a good day," said Danks, charged with seven runs (six earned) in 6 1/3 innings. "I didn't help myself out much, and I wasn't ahead in the count enough to really make them hit my pitch. So, I've got to get better."
The Angels scored twice in the first on Juan Rivera's RBI single and a throwing error by third baseman Gordon Beckham.
Mathis' two-run homer -- his fifth -- and a sacrifice fly by Aybar after Howard Kendrick's single handed Santana a 5-0 lead in the second. Right fielder Jermaine Dye lost count of the outs after handling Aybar's shallow fly and drew a Bronx cheer from the crowd.
After Guerrero lowered the boom leading off the fourth, Abreu's milestone homer -- No. 250 of his career -- came leading off the fifth.
"It's going to be exciting when the man gets hot," Abreu said, referring to Guerrero. "We're all going to get on base, and he's going to drive in a lot of runs and we're going to score a lot of runs. When he and Torii Hunter both come back, the length of the lineup is going to be stronger."
Abreu joined Willie Mays, Rickey Henderson, Barry Bonds, Joe Morgan and Craig Biggio as the only players in history with at least 250 homers, 2,000 hits, 1,000 runs scored, 1,000 RBIs and 300 steals.
"It surprised me, I didn't even know," Abreu said. "I don't really check the numbers. When they told me I needed one more homer to get in that group, I was excited. Those guys -- Willie Mays, Rickey Henderson, Bonds -- I'm happy to be in that group."
Santana surrendered a three-run homer to Jayson Nix in the second inning and walked home a run in the third. Composing himself, the right-hander struck out Nix looking on a full count and retired Chris Getz on a comebacker to the mound to leave the bases loaded.
After that, Santana exhaled and pitched effectively, retiring the side in order in the fourth and fifth. He escaped one final jam in the sixth, striking out Ramon Castro and retiring Scott Podsednik on a fly ball to leave two runners stranded.
In his best effort since yielding one run on three hits in eight innings at Oakland on July 16, Santana finished with seven strikeouts and five walks in six innings, allowing five hits and four earned runs.
"I was more confident today," Santana said. "I was throwing 3-2 sliders, changeups. I was confident in every pitch."
The Angels added a run in the seventh on Kendry Morales' RBI single, but ran themselves out of a potential big inning when Aybar was trapped in a rundown and tagged out at third.
Morales, the American League Player of the Week after abusing Minnesota pitching over the weekend, ended an 0-for-10 drought when he lashed his run-scoring single to right-center.
Aybar unloaded his fourth homer of the season in the ninth, wrapping up a big day that included two other hits, two runs scored, two RBIs and some quality work with the glove.
"Offensively, Erick had a good day," Scioscia said, "and defensively, he made some plays that were not routine look routine."
After Jason Bulger worked two perfect innings, silencing the Sox in the seventh and eighth, Kevin Jepsen surrendered a two-out homer in the ninth to pinch-hitter Dewayne Wise.
The Angels head home following a 4-2 road trip to engage the Rangers three times this weekend. Joe Saunders gets the call in Friday night's series opener at Angel Stadium, facing Texas right-hander Scott Feldman.
The Rangers have taken seven of nine from the Angels this season, including two of three in Anaheim.