Santana (8-8) scattered seven hits through 8 1/3 innings, but allowed just one run to earn his fifth straight decision. He walked one and struck out seven.
"I had command of every pitch. Everything felt good," Santana said of his performance. "I knew I could finish the game, but that was [Angels manager] Mike [Scioscia's] call."
Jordan Walden recorded the final two outs of the game to earn his 25th save of the year in the Angels' third win in their last four games.
Felix Hernandez (10-10) tossed his third complete game of the season, but it came in a losing effort. He allowed two runs on four hits with 12 strikeouts in just the second loss in the last six games for the Mariners.
Mark Trumbo put the Angels ahead in the third inning when he led off the frame by crushing a 471-foot home run over the wall in left-center.
"I knew I hit it good. I felt I caught it clean" Trumbo said about his home run. "It was nice to help us get the win."
Trumbo's homer was the only hit allowed by Hernandez until Howie Kendrick led off the seventh with a base hit. Torii Hunter followed with a single to put runners on the corners and, after a Bobby Abreu pop up to the right side of the infield, Vernon Wells hit a liner into shallow left field that scored Kendrick to give the Angels a 2-0 lead.
That insurance run would be needed, as Mike Carp hammered a solo homer with one out in the ninth inning, ending Santana's day.
Walden then took the bump and induced a pop up to short by Casper Wells and fanned Josh Bard on three pitches to end the game.
Seattle had a chance to take the early lead in the top half of the third. Back-to-back singles by Kyle Seager and Ichiro Suzuki put runners on first and third with one out. Jack Wilson came up next and hit a ball to the right of the mound. Santana fielded the ball and threw home, where Bobby Wilson had the plate blocked perfectly and applied the tag on a sliding Seager.
Santana's wild pitch during a Dustin Ackley at-bat moved Suzuki and Wilson up to second and third, but Ackley fouled out to end the threat.
The only other inning Seattle put a runner in scoring position was the fourth, but they would again fail to push a run across the plate. Seattle ended the game 0-for-3 with runners in scoring position and left five men on base.
LA's starting pitchers have allowed three runs or less in 12 of the last 16 games...The Angels have won 12 of their last 14 series...The Angels went 1-for-4 with runners in scoring position and left two men on base.