Santana, whose unimpressive spring numbers hadn't reflected manager Mike Scioscia's approval of his work, put it all together in six scoreless innings of one-hit ball, striking out five while walking three.
A leadoff triple by Rob Bowen in the third inning brought out the resolve in Santana, who struck out Donnie Murphy with a wicked slider and Chris Denorfia with a changeup before getting Mark Ellis on a popup to end the threat.
"Nobody wants a guy to score," Santana said of leaving Bowen stranded.
Aybar made the defensive play of the day behind Santana, his teammate with Caribbean Series champion Licey of the Dominican Winter League.
After a one-out walk to Bowen in the fifth, Murphy sent a bullet to the left of Aybar that the athletic shortstop reached with quick feet and hands, triggering a double play turned by Howard Kendrick at second base.
"He's got skills," said Santana, who last season called Aybar the most athletic player on the team and nodded with affirmation on Wednesday.
Guerrero reached for a pitch down by his ankles and homered for the second consecutive day and for the third time this spring, matching Torii Hunter and Brandon Wood for the club lead. This one, following Gary Matthews Jr.'s fourth hit of the day, came after A's reliever Keith Foulke had knocked Guerrero down with a high, hard one.
"To me, that's 100 percent a home run on the next pitch," Santana said, adding that he's seen Guerrero pick himself up and crush the next delivery "a lot of times."
Santana had allowed 12 earned runs on 18 hits in 13 2/3 innings coming into his fifth Cactus League outing, but Scioscia remained supportive of his pitcher's performance.
"He's brought that same stuff into some games," Scioscia said. "He had his best results today, obviously. It's good to see him get that deep in a game -- 91 pitches, I think -- and be effective.
"Experience is a great teacher. Hopefully, his struggles last year weren't for naught with Ervin, and he understands more about his mechanics. He got in some bad habits last year. Hopefully, he got them cleaned up and he'll stay consistent."
Shaving his ERA to 5.49, Santana now has 16 strikeouts against six walks in 19 2/3 innings, the heaviest workload for an Angels pitcher this spring.
Santana is scheduled for two more starts this spring -- both against the Padres. This would keep him in line for a start in the fourth game of the regular season, the series finale in Minnesota on April 3.