Cano delivered a game-tying two-RBI double in the seventh and later scored the go-ahead run as part of a 2-for-3 performance. Chris Nelson also came through with a pair of hits and a run scored to help the Yankees post their seventh win in eight outings.
The comeback prevented Felix Hernandez from winning a fifth consecutive start after the star righty outdueled CC Sabathia in a clash of aces. Hernandez held New York to one run and five hits while striking out eight before exiting after six innings.
Charlie Furbush (0-2) was hung with the loss after permitting two runs and recording just one out in the seventh.
Sabathia racked up a season-best 10 strikeouts, but was reached for three runs -- two earned -- on 10 hits over 6 1/3 innings. Two of those runs came on a homer by former Yankee Raul Ibanez that put Seattle up 3-0 in the sixth.
Ex-Mariner Shawn Kelley (2-0) received the victory after retiring both men he faced in relief of Sabathia, with Mariano Rivera firing a 1-2-3 ninth to notch his 16th save in as many chances this season.
Ibanez finished 2-for-4 for the Mariners, with Kyle Seager contributing an RBI double in the setback.
Curtis Granderson returned to the New York lineup from a fractured right forearm sustained in late February, but went 0-for-3 with a walk and run scored in his season debut.
Hernandez, who was often wincing and stretching his back between batters throughout the night, departed after 97 pitches with his team holding a 3-1 lead that the Mariners' bullpen failed to hold.
"I wanted to send (Hernandez) back out there, but I have to be smart and take care of him and not put him in harms way," Mariners manager Eric Wedge said.
Nelson greeted Yoervis Medina with a single to begin the Yankees' seventh- inning rally, and Brett Gardner drew a one-out walk off Furbush in front of Cano, who drove a double off the base of the wall in right center to plate both runners and knot the score.
Two more walks issued by Furbush loaded the bases, with Overbay lofting a fly ball to center that sent Cano home and put the Yankees in front.
Seattle got the potential tying run in scoring position in the eighth after New York reliever David Robertson walked Dustin Ackley and Brendan Ryan followed with a sac bunt. However, Robertson struck out Michael Saunders and Ackley was doubled off second on a line drive to short by pinch-hitter Justin Smoak.
Rivera then needed just 11 pitches to mow down the Mariners in order in the ninth.
"It's pretty special...to watch him up close in action and go about his business," Kelly said of Rivera.
With both former Cy Young Award winners near the top of their games early on, the only run produced over the first five innings came as the result of a Yankees' error in the top of the third.
Overbay mishandled Saunders' grounder to first, with the miscue proving costly when Seager stroked a two-out double into the right-center field gap to give Seattle a 1-0 edge.
That changed in the sixth. After Kelly Shoppach singled to lead off the frame, Ibanez -- one of the heroes in the Yankees' ousting of Baltimore in the ALDS last October -- clobbered a Sabathia fastball into the stands in right to extend the margin to 3-0.
Hernandez surrendered just three hits and fanned eight before Cano opened the Yankees' half of the sixth with a base hit. Two batters later, Overbay clubbed a double into the right-field corner to bring home Granderson, who reached on a fielder's choice that erased Cano off the paths.
Kelley pitched in 120 games over four seasons with the Mariners before being traded to the Yankees in February ... Including the playoffs, Ibanez now has seven homers over his last 10 games at Yankee Stadium dating back to Sept. 22 of last season ... Hernandez is 4-1 with a 1.18 ERA in six career starts at the new Yankee Stadium ... Seattle lost for the first time in 10 games this season when outhomering its opponent ... Yankees designated hitter Travis Hafner was held out of the lineup due to a sore right shoulder.
05/15 00:18:30 ET