The A's looked strong early as Coco Crisp had doubles in his first two at-bats off Padres pitcher Ian Kennedy and A's starter Sonny Gray tossed four scoreless innings.
Crisp, who started the spring 1-for-13, led off the game with a double to ignite a three-run inning and followed with an RBI double in the second to make it 4-0.
Gray didn't allow a hit until Will Venable singled with two outs in the fourth inning. Venable added a second hit in the sixth inning.
"Like I said after the D-backs start last week, today we were going to go in with a regular-season game plan, attack hitters and use all our pitches," Gray said. "That's what we were able to do and it went pretty well."
Kennedy pitched better after his rough first inning, when he allowed the Crisp double, a double to John Jaso and then a two-run home run to Jed Lowrie.
Kennedy's start on Tuesday looked a lot like his previous start on March 6 against the Rangers, when he allowed the first four hitters to reach base. He later retired eight consecutive hitters.
Facing the A's, Kennedy allowed four hits in the first inning, then a combined four hits over the next three innings with no runs. In all, Kennedy allowed four runs on eight hits with two strikeouts.
"He just got some balls up out over the plate," Padres manager Bud Black said. "He couldn't get the changeup down. I thought his curve was good. He ended up getting the changeup down the next couple of innings. He's going to pitch up and down. But he's doing fine. He's building his arm strength. His arm feels great. He's getting into April shape."
Lowrie had two hits and Josh Reddick knocked in a run with an RBI single in the fifth inning off Padres reliever Robbie Erlin.
Jedd Gyorko knocked in a run for the Padres with a sacrifice fly in the sixth inning.
Up next: The A's will return to Phoenix Muni on Wednesday when the club hosts the Royals for 1:05 p.m. PT start in an exclusive webcast on athletics.com. Scott Kazmir, signed to a two-year, $22 million deal in the offseason, will make his second Cactus League start, following an impressive debut last week. Facing the D-backs, Kazmir allowed two hits and no runs while striking out two over three innings of work. Sean Doolittle and Jim Johnson are also scheduled to pitch Wednesday while Derek Norris (back spasms) could return to the lineup for the first time since March 4.