Alex Rodriguez got hit by a pitch after he homered, and Curtis Granderson and Mark Teixeira also went deep.
Colon struck out six and gave up only two hits against his first major league team before he had to come out on Shin-Soo Choo's grounder to first.
Colon (5-3), famously traded in 2002 by the Indians for three minor leaguers who went on to become All-Stars, struck out six over 6 2/3 innings to win for the third straight start after two losses in his previous five.
The Yankees, who have already lost starter Phil Hughes to a shoulder injury, will have to wait and hope for the best with Colon, who has been a key starter for them so far this season. He lowered his ERA to 3.10, best in the rotation.
"Bartolo is throwing like a legit No. 1 starter in the AL East," Rodriguez said. "A1A stuff."
A-Rod was in the middle of the action on Saturday. He was hit by a pitch after he homered the previous time up, and shortly after Granderson hit his 20th of the season. The two sluggers both homered against Cleveland the night before.
"I don't know if it was intentional, but it hurt like hell," said Rodriguez, who said he was hit in the IT band between his hip and knee.
Plate umpire Dan Iassogna immediately tossed Mitch Talbot after the righty hit Rodriguez. While A-Rod writhed on the ground, Talbot argued with Iassogna, and Cleveland manager Manny Acta came out, too. Talbot gestured to the mound, and said he told Iassogna that he slipped while throwing the pitch.
"After the situation we had last night, and Alex hit a big home run last night and hit another home run today, and Curtis Granderson hit a home run last night and another one today, he threw the pitch directly at him," Iassogna told a pool reporter.
Talbot thought it was a bit harsh.
"I've never been one to hit somebody because they got a home run or for doing their job. I don't believe in that," Talbot said. "I thought it was a little ridiculous. Honestly ... I got tossed because Texeira got hit yesterday. If you take that away and I hit A-Rod today, even after the home run I don't think I get tossed."
Acta was miffed, too.
"When is the right time to slip? With anybody else at the plate?" Acta said. "I mean so anybody else would have gotten it and no problem. I felt that that was uncalled for."
It was the sixth time a Yankees batter has been hit this homestand.
The Yankees sent Cleveland to its 13th loss in 17 games and left the Indians barely clinging to first place in the AL Central.
The Yankees made it 3-0 in the seventh when Jorge Posada singled into the right field corner. Choo had trouble coming up with the ball and Nick Swisher came home.
The Indians got the tying run to the plate with nobody out in the eighth, but David Robertson struck out Michael Brantley, Asdrubal Cabrera and Grady Sizemore to end the threat.
Teixeira homered off Vinnie Pestano in the eighth to make it 4-0.
A-Rod opened the scoring in the fourth inning with a line-drive shot into a strong wind blowing in from left field for only the second hit off Talbot (2-3). Granderson then hit his 20th homer of the season deep to right in the sixth.
Teixeira left Tuesday night's game against Boston after getting hit on the right kneecap by a first-inning pitch from Jon Lester, and Red Sox ace Josh Beckett plunked three New York stars Thursday night: Jeter, Rodriguez and Granderson.
"I'm tired of it," Girardi said. "Our guys get hit entirely too much. We're a club that hits home runs and people don't necessarily like that."
Girardi added: "We'll protect our own."
Game notes
Granderson tied Toronto's Jose Bautista for the AL lead in homers. Teixeira is one behind with 19. ... Hughes threw off a bullpen mound at the Yankees' complex in Tampa, Fla. He is scheduled to pitch Tuesday in a minor league camp game. ... Brett Gardner got the Yankees' first hit off Talbot with a bunt single in the third inning. He was thrown out at second on a pitchout, and Talbot caught him trying to steal third in the fifth. ... In the second inning, the Yankees' Robinson Cano hit a liner foul and it hit a police officer stationed in the photo well. He disappeared from view briefly, then reappeared to applause, and his fellow officer smacked him on the back as he triumphantly showed the ball. ... The Indians received Sizemore, Cliff Lee and Brandon Phillips from Montreal in the 2002 deadline trade for Colon.
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