On a chilly, rainy night in the Bronx, Cano received a mixed reception from the fans who had cheered for him for nine years before he signed a 10-year, $240 million deal with the Mariners last offseason.
Cano was limited to one hit in five at-bats and struck out twice, but his new teammates picked up the slack, most notably Mike Zunino, who went 4-for-5 with a run scored and an RBI.
Corey Hart knocked in a pair during a four-run fifth inning, and Chris Young (1-0) held the Yankees to two runs -- one earned -- on three hits and three walks over 5 2/3 innings to earn his first win since Sept. 2, 2012.
CC Sabathia (3-3) lost to the Mariners for the first time in 10 meetings after surrendering four runs on nine hits over five-plus innings.
New York brought the tying run to the plate in the ninth following Brett Gardner's RBI single, but Fernando Rodney struck out Derek Jeter and Carlos Beltran to secure Seattle's fourth win in five games
Cano brought in the first with a bases-loaded groundout, Hart's inside-out swing found the right-field gap to bring in two more and Justin Smoak capped the rally with an RBI single.
Dellin Betances took over for Sabathia in the sixth and retired three straight to strand runners on second and third, but Seattle tagged the reliever for a run in the seventh on Dustin Ackley's two-out base hit.
Preston Claiborne then replaced Betances on the mound and served up a single to Kyle Seager before Zunino scored Ackley with a single to right to make it 6-2 Seattle.