Lackey (4-1) went 7 2/3 innings and shut down the Mets after they seized a first-inning lead on two ground-ball singles and a double-play grounder by David Wright.
Hunter for eight seasons was on Santana's side with the Twins. Facing his old Minnesota buddy for the first time, Hunter lashed the first pitch he saw, a waist-high changeup for a two-run double in the bottom of the first. An unearned run followed, and Lackey was in control for keeps.
"He left a changeup up, and I said, 'Thank you,'" the effusive Hunter said. "He was looking at me when I came up and had to step off the mound."
Santana had something to say to Hunter as he rolled into second, with Garret Anderson and Vladimir Guerrero scoring on his drive into the left-field corner.
"When I hit the double and was at second," Hunter said, "I think he said, 'I hate you.' It was all in fun. I miss him. I love him."
Santana said he "didn't throw the pitch that was supposed to be thrown, and that cost us a few runs. I know how he is. He's a great hitter.
"We played together for eight years, so it was nice to see him. At the same time, we're on different sides, and I wanted to get him out. He swung at the first pitch and hit it to the right spot."
Hunter was looking to drive a fastball to right-center and adjusted to the changeup.
"Johan is one of those guys who comes after you, no matter who you are," Hunter said. "You can't try to do too much with a guy who has the changeup he has. We were patient, and it paid off."
In front of 40,122 at Angel Stadium, the Angels jumped on Santana (7-5) for three runs in the bottom of the first.
Hunter followed Maicer Izturis' single and Guerrero's double with his two-out double, scoring when first baseman Carlos Delgado mishandled Casey Kotchman's grounder for an error.
The Angels added a run in the third with two outs when Guerrero singled, Hunter walked and Kotchman -- winning a protracted duel with Santana -- slashed an RBI single to center.
In the sixth, catcher Jeff Mathis unloaded a solo homer to left-center, his fifth of the season.
Santana departed having yielded five runs (four earned) on eight hits in six innings. This was the least productive of his 15 outings with the Mets. He'd given up four earned runs twice, but he lasted deeper in those games.
"Our guys swung the bats well tonight," Lackey said. "It should be a confidence booster for our offense. They really did well against a great pitcher."
Lackey was superior, surrendering six hits and walking one man -- the last hitter he faced -- while striking out seven. In the sixth, with a runner in scoring position, he reached back and struck out the side, including Wright looking.
"I did that?" Lackey said, grinning, when asked if that was his highlight for the night. "You've got to figure out what's going good that night and go with that. I had a pretty good breaking ball and was able to throw it for strikes.
"They've got a tough lineup. You can't give in; you've got to keep changing things up."
The big Texan is back at the top of his game after a brilliant 2007, making his first All-Star team, winning the American League ERA title and finishing third in the Cy Young Award balloting with a career-best 19 wins.
"That was a terrific performance," manager Mike Scioscia said of Lackey's gem. "That's one of the best efforts we've seen from John, and he's been consistent all year."
His ERA fell to 1.73 as he yielded one run for the fifth time in seven outings, going at least seven innings each time.
Reliever Scot Shields left two Lackey runners stranded in the eighth, claiming his second save with four outs of relief.
The Mets lost Jose Reyes, their brilliant shortstop, with a stiff left hamstring after he singled leading off the game. Pinch-runner Damion Easley moved to third on Luis Castillo's single and scored when Wright hit into a double play.
"A lot of times when you go against a guy who's really good," Lackey said, "you don't want to give up the first run, which I did. My focus over the last year -- things I've learned on how to get out of tough spots -- it's come together."