Santana went 6 1/3 innings and allowed two runs on five hits. He struck out four against two walks and threw 100 pitches.
"Everything was working for me tonight," Santana said. "I kept the ball down and elevated when I wanted to, and my offspeed stuff was very good, too. We started scoring some runs and it built my confidence up."
Santana consistently got ahead in the count and kept the Red Sox guessing.
"He pitched a terrific game. I think his location was good, he was hitting his spots -- which is when he's at his best," Angels manager Mike Scioscia said. "For the most part it was about command, and he had a good changeup, too, which he mixed in, and had his breaking ball all night."
The Halos improved to 5-0 in Santana's last five outings. The right-hander is 3-0 with a 3.52 ERA during that span. Since July 28, the Angels are 3-15 when anyone else starts. They entered Tuesday's game with a 6.51 ERA in August.
Before Santana's string of solid outings, the Angels had lost his five starts from June 23-July 21. But the club knew he would eventually turn things around.
"We saw it in Ervin and saw the potential he has," Scioscia said. "He was on just a tough roll where he really just didn't have a lot. But Ervin has done it before. We've seen him bounce back after some tough starts, and the run that he had, that was a little longer than we've seen, but we have a lot of confidence in him."
Mike Trout hit two singles and scored a run. The center fielder has 97 runs through 100 games this season, the second most by a rookie in that span in the modern era (since 1900), and the most since Joe DiMaggio had 100 in 1936.
Mark Trumbo crushed a two-run homer over the Green Monster in the fifth inning to give the Angels a 5-0 advantage. It was the 30th home run of the season for Trumbo, a career high. He turned on a 3-2 offering from starter Aaron Cook and sent it out of the ballpark for his first long ball since Aug. 8 at Oakland.
"That ball was absolutely killed," Scioscia said.
Trumbo is the first Angels player with at least 30 homers in a season since Kendrys Morales hit 34 in 2009. He's homered in each of his three career games at Fenway Park, joining Cleveland's Jason Kipnis as the only Major Leaguers since 1918 to accomplish that feat.
Trumbo entered the game hitting .200 in August, with two homers and no doubles. He singled in his first at-bat and said he's starting to feel better at the plate.
"It just feels more like my swing," Trumbo said. "I always try to drive the ball; maybe my swing was over-aggressive, so I tried to tone it down a little bit."
The Angels got to Cook the second time through the lineup. His sinker was not sharp and he lost for the fifth time in his last six starts. The veteran allowed five runs on 11 hits over five innings.
"They've got a really tough lineup," Cook said. "I felt like I was making pitches, they were just finding holes with those singles. Being a sinkerball pitcher, you kind of live off whether or not they hit the hole or hit it at your infielders. They were able to string together a few of those in the holes, and I left one pitch up on a 3-2 to Trumbo and he hit it about as hard as you can hit a baseball."
The Angels got on the board in the third inning on an RBI single by Albert Pujols.
Playing at Fenway Park for the first time since Game 2 of the 2004 World Series, Pujols had two hits, including a double off the Green Monster in his first at-bat. He was 3-for-4 with two doubles and a run scored in that World Series game, when he was a member of the Cardinals.
Santana got himself out of a jam in the third inning. With two outs and runners on the corners, the right-hander struck out Adrian Gonzalez, who leads the Major Leagues with a .406 average with runners in scoring position.
Santana's only blemish came in the sixth inning. After a two-out walk to Cody Ross, he served up a two-run homer to Jarrod Saltalamacchia. But Santana gathered himself and struck out Daniel Nava a second time to end the frame.
"He was throwing strikes, getting ahead of guys," Trout said. "They didn't look too comfortable against him."