Nate Freiman had two hits and an RBI in his major league debut as Oakland knocked around Joe Saunders and two relievers after managing just one run and six hits in the first two games of the series.
Franklin Gutierrez and Michael Morse homered in the first, but Milone settled down and retired 17 of his final 18 batters while pitching seven innings. It was the third homer in two games for Morse, a key offseason acquisition for the Mariners.
Lowrie, acquired in a trade from Houston just before the start of spring training, went 3 for 3 with a walk and three RBIs. His tiebreaking two-run double off Saunders in the fourth put the A's ahead for good.
Oakland had seven extra-base hits overall: five doubles and two home runs. Eight A's had at least one hit while four drove in at least one run.
It was quite a difference from the first two games, though manager Bob Melvin didn't seem too concerned with his club's slow start.
Milone (1-0) allowed only one baserunner after the second inning, finishing with one walk and four strikeouts. Sean Doolittle pitched the eighth and Chris Resop worked the ninth to complete the five-hitter.
Gutierrez got the Mariners off to a nice start when he hit the fourth pitch from Milone over the wall in left for his second career leadoff homer. Morse, who led the majors with nine home runs in spring training, tacked on a two-out drive to center.
Freiman's first career hit got Oakland on the board in the second. But the rookie first baseman was thrown out at the plate trying to score on Scott Sizemore's double to left.
Freiman later singled in the fourth then made a sliding catch in front of the photographer's well near Seattle's dugout in the fifth.
Saunders (0-1) ran his pitch count up in the third when he yielded a leadoff double to Coco Crisp, then walked Lowrie and Young. Yoenis Cespedes drove in Crisp with a sacrifice fly to center, but Saunders limited the damage from there.
The A's went up 4-2 in the fourth on Lowrie's double to left-center after Josh Reddick doubled and Crisp reached on a fielder's choice.
Lowrie and Young added consecutive home runs off Kameron Lowe in the seventh.
Milone, tied for the team lead in wins as a rookie last season, and two relievers did the rest.
Milone gave up a leadoff single to Jesus Montero in the second, then walked Jason Bay before getting Robert Andino to hit into a double play. Seattle didn't get a runner past first base the rest of the game.
NOTES: Sizemore went 1 for 4 in his first game since he injured a knee on the first day of spring training in 2012. ... Saunders lasted four innings and allowed seven hits with four walks. ... Seattle has not started a season 3-0 since 1995. ... The A's claimed RHP Will Harris off waivers from Colorado and optioned him to Triple-A Sacramento. To make room on the 40-man roster, RHP Josh Stinson was designated for assignment. ... RHP Brendan Maurer will make his major league debut for Seattle on Thursday. He'll oppose Oakland RHP A.J. Griffin, who went 2-0 with a 1.64 ERA in two starts against Seattle in 2012.