Colon (5-3) was breezing through the Indians' lineup, yielding only two hits and one walk while striking out six, before straining his left hamstring while covering first base on a groundout by Shin-Soo Choo.
David Robertson escaped a two-on, none-out jam in the eighth and Boone Logan tossed a scoreless ninth to complete the shutout, which sent the Yankees to their 12th win in 15 games over the Indians.
Curtis Granderson hit his 20th homer -- tied with Toronto's Jose Bautista for the American League lead -- Mark Teixeira added his 19th and Alex Rodriguez also went deep in the Yankees' win.
Mitch Talbot (2-3) absorbed the loss after allowing two runs on four hits over 5 2/3 frames.
The right-hander was ejected from the game after hitting Rodriguez with a pitch, bringing a vehement argument from Cleveland skipper Manny Acta. The manager argued Talbot had merely slipped on a rain-soaked mound while delivering the pitch.
The AL Central-leading Indians dropped their 13th game in 17 contests.