With his first loss in seven decisions, Santana was thwarted in his bid to join Jered Weaver and Aaron Sele as the only pitchers in club history to start a season 7-0.
The win went to southpaw Hong-Chih Kuo (3-1) in relief of Chan Ho Park, who held the Dodgers to two runs in four innings in his season debut as a starter. Park hadn't made a start since April 30, 2007 with the Mets.
"Everything is good -- very good," Santana said, alluding to his mechanics and his stuff. "If it's seven runs I'm giving up, I'd have to worry about it. I'm perfectly fine. I'll just get after it next time and throw strikes."
His command -- three walks and a hit batsman -- was less than flawless, but as the man was saying, nobody's perfect.
Asked if the heat bothered him, Santana smiled and said, "I'm from the Dominican Republic. It's hot there, too.
"They made me work a lot. They don't swing at a lot of pitches. They're patient."
Blake DeWitt's two-run homer in the second following a walk to Andruw Jones put the Dodgers in front.
"He retired five in a row and had strike one on Jones and lost him," Angels manager Mike Scioscia said of Santana. "One pitch to DeWitt, and it's 2-0."
Santana said he was "trying to get ahead of DeWitt with a fastball away -- I just had a two-out walk -- and he took a good hack."
Scioscia disputed the home run. He thought a fan reached down and interfered with the ball from the right-field seats, and for the third time in the series it brought him charging out of the home dugout.
First-base umpire Gerry Davis explained to Scioscia that he saw the fan reach for the ball, but thought it had cleared the wall any way.
The Dodgers doubled their lead with two in the third on RBI singles by Andre Ethier and Russell Martin after a walk to No. 9 hitter Chin-lung Hu and hit batsman (Juan Pierre).
The Angels cut the lead in half against Park in the fourth, his final inning. After Vladimir Guerrero was hit by a pitch, Anderson singled him to third.
Hastening to make a double play on Casey Kotchman's grounder, first baseman James Loney launched his throw over Hu, the shortstop covering second, and into left field. Guerrero scored, Anderson moving to third. Maicer Izturis' fielder's choice grounder scored Anderson, but Park found the right stuff to shut down the threat.
Santana made it through six innings, giving up four earned runs on five hits and three walks while striking out five. An error by Izturis at second led to an unearned run in the seventh against Darren Oliver, Pierre scoring from third when Martin was trapped in a rundown.
"They've been geared for years to take the extra base," Pierre said. "Today, we had a chance to do it, and we took advantage of it. We weren't really knocking the cover off the ball. Russ got all the hits, pretty much."
The Dodgers scored in the eighth on DeWitt's double and Luis Maza's RBI single against Chris Bootcheck. Juan Rivera's pinch-hit double and Erick Aybar's single got the Angels a final run against Takashi Saito in the ninth.
It was just the second win in the past 11 Interleague visits to Angel Stadium for the Dodgers, whose new manager, Joe Torre, is 1-1 against the Angels.
Apart from Anderson, hitting .536 during a seven-game streak and .444 over the past 12 games, the Angels are searching for offense with Chone Figgins and Howard Kendrick sidelined. They've lost seven of the past 10 and are 6-7 without Figgins.
Pierre can see the Angels aren't the same dynamic offensive force without his good buddy Figgins, with whom he broke into the game in the Rockies' organization.
"He's that sparkplug, the guy who gets things going," Pierre said. "I'm sure when teams make their scouting reports, a big thing is keeping Figgins off the bases. He makes it easier for Vlad and Garret and those guys coming up behind him.
"Chone's that sparkplug for his team, offensively and defensively."
Figgins has been out since May 4 with a strained right hamstring, and the offense has been hamstrung in his absence at the top of the order. Kendrick's .500 bat (18-for-36) has been in storage since April 13, when he strained his left hamstring running the bases.
Figgins is eligible to come off the disabled list on Tuesday when the Angels kick off a six-game road trip in Toronto. Kendrick, who has had a setback with his hamstring, appears to be at least a week away.