Colon pitched into the seventh inning to earn his first win in two years and the Yankees beat the Toronto Blue Jays 6-2 on Wednesday night.
"It's very special for me," Colon said through a translator. "The shoes that I wore today, I'm going to keep them as a memory."
Curtis Granderson homered for the AL East-leading Yankees, who won for the fifth time in seven games and remain the only major league team without consecutive losses this season.
New York leads the majors with 30 home runs.
The Dominican right-hander said he wasn't sure he'd ever make it back to the majors after personal struggles in 2009.
"I had a lot of problems, I had family issues," he said. "I never thought I was going to come back and play baseball again."
Colon struck out seven and walked two in his first major league start since July 24, 2009, for the White Sox. The 2005 AL Cy Young Award winner improved to 9-3 with a 3.60 ERA in 19 career games against the Blue Jays.
"Outstanding job by Bartolo, keeping his pitch count down, getting big outs for us," manager Joe Girardi said.
David Robertson pitched an inning, Boone Logan and Lance Pendleton each got one out and Rafael Soriano finished for his first save one night after closer Mariano Rivera had his first blown opportunity of the season.
Alex Rodriguez returned to the Yankees' lineup after missing the previous two games because of soreness in his left side. He walked twice and had a sacrifice fly in his first three plate appearances before striking out swinging in the seventh and going down looking in the ninth.
"Definitely a big relief for me just to get through the day," Rodriguez said.
Granderson hit a solo homer in the ninth, his second in as many games and sixth overall. He went 2-for-4 with two RBIs.
"We always knew he had a lot of power," Girardi said. "I think what you're seeing is more consistent contact, hitting the ball harder on a consistent basis."
The Yankees added two more in the second on an RBI triple by Granderson and a run-scoring grounder by Derek Jeter.
Toronto catcher J.P. Arencibia led off the bottom half with a drive off Colon, who responded by retiring the next 12 batters.
"He threw the fastball all the way from 87 to 95 and the ball moves all over the place," Rodriguez said.
New York padded its lead and chased Cecil with a two-run fifth, with Rodriguez and Cano hitting consecutive sacrifice flies.
The Blue Jays got one back in the seventh but a baserunning mistake cost them a chance for a second. With one out and men at first and second, Travis Snider lined a single to right. Edwin Encarnacion stopped at third but Arencibia rounded second and ran all the way to third, where he was tagged out by Teixeira.
Robertson replaced Colon and gave up an RBI single to Nix but struck out McDonald to end the rally.
The Blue Jays activated RHP Brandon Morrow (elbow) off the 15-day disabled list and optioned LHP Luis Perez to Triple-A Las Vegas. ... Granderson's homer came on the first pitch of the season by RHP Frank Francisco. He started the year on the DL with a sore shoulder and was activated Tuesday. ... Yankees RHP Mark Prior was placed on the minor league DL with a strained groin. Prior is at Triple-A Scranton/Wilkes-Barre. ... Yankees RHP Phil Hughes (dead arm) threw a 30-pitch bullpen session before the game, the first time he'd thrown off a mound since Apr. 14. Hughes will throw another bullpen Friday. ... Toronto 2B Aaron Hill (right hamstring) was held out of the starting lineup. Nix started at second and McDonald played third. ... Toronto's Juan Rivera, who is batting just .103, has been dropped from the designated hitter role, manager John Farrell said. Encarnacion will take over as DH.