Santana (2-7) went 4 2/3 innings in the loss, his shortest outing since May 4 of last season and allowed seven runs, the most since he allowed nine to the Orioles in 2010. His seven losses are tied for the most in the American League.
Santana's continuing troubles came on a night the Angels got a couple of big-time offensive performances. Kendrys Morales clubbed two home runs and Mike Trout went 4-for-4 with two RBIs and a run scored, extending his hitting streak to nine games.
Angels starters have allowed more than three runs in an outing just four out of their last 21 games, and in three of those four starts, Santana was the pitcher.
"He just hasn't unlocked that delivery that's going to let him repeat pitches," manager Mike Scioscia said. "He's not throwing the ball anywhere near his potential right now."
Over his last three starts, Santana has an ERA of 10.43, allowing 17 runs and 14 walks in 14 2/3 innings.
Down 3-2 in the fifth inning, Santana got two quick outs and looked to be settling in, but after allowing three hits and two walks, one intentional, the Angels' deficit grew to five. The big blow came on a three-run double from nine-hole hitter Munenori Kawasaki.
"He had two out, nobody on, and then he just kept going the wrong way," Scioscia said. "We thought he could finish that inning off and keep us in the ballgame."
The Angels did have an opportunity to come back later in the game in the eighth inning, when down by two with men on second and third. But Tom Wilhelmsen induced Albert Pujols into a fielder's-choice comebacker and then got Mark Trumbo to strike out for the fourth time in the game.
In total, Angels hitters struck out a season-high 14 times, eight of which came against Mariners starter Jason Vargas (7-4), who tossed 5 2/3 innings, giving up four runs on nine hits and two walks in the win.
Two of those four runs came off of Morales' fifth and sixth home runs of the year. It was Morales' seventh career multi-home run game and first of the season for the Angels and also Morales' first and second while batting right-handed this season.
"You throw him six changeups in a row and then throw him a fastball down in the strike zone 3-2, and he puts that kind of swing on it, you have to tip your hat," Vargas said. "I think I threw him two pitches away the whole night, then he stayed on that last one and hit it out again. I don't know. You just have to move on."
Trout also had a career night, going 4-for-4 and raising his batting average to .338, which leads all rookies and would be sixth in the AL if he had enough at-bats to qualify. His first-inning double extended his hitting streak to nine games and gave him an extra-base hit in six of his last seven.
"Mike's been as consistent as anybody we have out there, for sure," Scioscia said. "There's no doubt that he's pulling his share-plus."
Along with losing the game, the Angels were without catcher Bobby Wilson from the second inning on, when he left the game after taking a foul ball to the mask in the first inning.
Wilson came in to catch the top of the second, but was taken out for precautionary reasons. He has a concussion back in April 2010 after a collision at home with Yankees first baseman Mark Teixeira that sent him to the disabled list.
The Angels are already without catcher Chris Iannetta (fractured wrist) and may be forced to call up a player if Wilson is forced to miss extended time, but Scioscia said he'll wait until Tuesday to see how Wilson feels before making any decisions.
"He really was a little woozy," Scioscia said. "With his history, he had a concussion a couple years ago, we're going to be very cautious and see where he is tomorrow."