"The only way to beat good pitching is with good pitching," Angels manager Mike Scioscia said after Colon outdueled Santana, who gave up two hits in eight innings but saw his 20-game unbeaten streak snapped.
Colon (4-2) was outstanding until he had to leave the game with one out in the eighth when he tweaked his left ankle after he jumped for Jacque Jones' bouncer over his head.
After the game, Colon said through an interpreter that he expects to make his next start, Saturday at home against Detroit.
"It's not as bad as I thought it was when I first came out of the game," said Colon, who landed awkwardly on the slope of the mound.
Reliever Scot Shields replaced Colon and gave up a single to Michael Cuddyer and walked pinch-hitter Joe Mauer to load the bases, but Francisco Rodriguez took over and got Matthew LeCroy to hit into an inning-ending double play.
"I wanted the strikeout there," Rodriguez said. "I was trying to throw him a slider up and in and get ahead in the count, then go with my best pitch, the slider down and away. But he was cheating, trying to get ahead and drop the head of the bat, and it didn't work out for him."
Shannon Stewart led off the ninth with a home run, but Rodriguez retired the next three hitters to earn his sixth save.
But give the game ball to Colon, who retired the first nine Twins, all on ground balls, and allowed just two measly baserunners on the day -- a soft single to right by Shannon Stewart in the fourth, and Jones' chopper that knocked him out in the eighth. He mixed his two-seam and four-seam fastballs and kept the Twins off-balance by getting ahead in the count consistently.
"He was throwing a lot more two-seamers," said the Twins' Torii Hunter. "I've been playing against this guy forever, and tonight was the best I've ever seen him. If he stays that way, he's going to be one of the front-runners for Cy Young this year."
Afterwards, Colon spent more time praising his catcher and opponent than reflecting on his own work.
"Jose Molina was perfect today," Colon said of the Angels' backup backstop. "He gave me a target, and it seemed like every time he put the glove down, he was thinking the same as me."
Meanwhile, Santana (4-1) was almost as strong, but both hits he allowed were solo home runs, and that was enough for Colon and the bullpen to put a stop to his team-record streak, which included 17 wins and three no-decisions.
"That's a mark any pitcher would like to have, and I congratulate him on it," Colon said. "I give Johan a lot of credit for a magnificent game today. It's always a good challenge. With the guys I'm sometimes paired up against, I really have to bear down because I know they're going to be tough on our hitters."
Both pitchers were in control from the start, each facing the minimum through three innings. But with two outs in the fourth, the Angels finally broke through as Vladimir Guerrero, who was 0-for-7 lifetime against Santana, blasted a towering fly ball down the line in left field. It struck the foul screen 30 feet up for a home run, Guerrero's team-leading sixth of the year, and a 1-0 Angels lead.
Molina doubled the Angels' lead by lining Santana's first pitch of the sixth inning over the fence in left-center field for his first home run of the season. Otherwise, Santana issued a pair of harmless two-out walks as he and Colon matched each other pitch for nasty pitch.