The shot came with two outs in the bottom of the 10th inning off Chicago left-hander Randy Williams, marking the Yankees' 12th walk-off victory of the season -- their highest total since 1978 (13).
And it was big for Cano, who has struggled with runners in scoring position despite compiling what he believes is his best campaign to date, including leaving the bases loaded in the fifth inning on a grounder to the mound.
"I was looking for something right in the middle," said Cano, who admits he has been tracking his RISP average on the scoreboard. "I've been struggling with men on base, and I just wanted to do something where I could go up and swing the bat."
Yanks manager Joe Girardi said that regardless of Cano's highs and lows -- he was also robbed on a line drive Thursday that cost the Bombers multiple runs -- there continues to be a good feeling when Cano comes to the plate.
"The thing about Robbie is, he's going to put the ball in play," Girardi said. "A lot of times, he's going to hit it hard. He hasn't had the most luck this year of guys. But he put a great swing on that ball, and it was a no-doubter when he hit it."
With Cano rounding third base and being mauled at home plate, slugged in the face with the customary Yankees shaving cream pie, the exciting finish came after Derek Jeter and Johnny Damon had each homered earlier off White Sox starter Mark Buehrle.
New York's bullpen fired three shutout innings in relief of CC Sabathia, who provided the Yankees with six scoreless frames before running into trouble in the seventh and escaping with the tie intact on a strong throw by Nick Swisher.
"I really can't be too upset," said Sabathia, who threw 113 pitches and remained undefeated in his past six starts. "They put some good at-bats together; give them credit."
With New York leading by two runs on the solo homers, Sabathia appeared primed to become the Major Leagues' first 16-game winner, but Jermaine Dye interrupted the cruising Sabathia by opening the seventh with a double.
After a walk, Dye came around to score on an Alex Rios double, cutting the deficit to 2-1 as Sabathia began to have difficulty spotting the fastball and changeup that served him so well.
Sabathia got the first out on a hot line drive to Cano at second base, and Alex Rodriguez made a smart play on Ramon Castro's one-out grounder to third, throwing home to easily nail Carlos Quentin on a fielder's choice.
But Laynce Nix placed an infield hit down the third-base line, saved only by a diving A-Rod stop, and Gordon Beckham lined a full-count pitch into right field that scored Rios with the tying run.
Swisher scooped the ball off the wet outfield grass, and, spotting the slow-footed Castro being waved home, uncorked a fine throw to the plate that catcher Jose Molina gobbled. Planting a bare-handed tag on the sliding backstop, the play ended the inning and preserved the tie.
"CC's been our guy, there's no doubt," Swisher said. "When we're out there, we give him the best of what we've got."
Sabathia is 5-0 with a 2.64 ERA in his past six starts, and he matched a season high with 10 strikeouts. He said that Friday was a good continuation of all the things he has done well in August.
"I'm pounding the strike zone," Sabathia said. "That seventh inning got away from me a little bit there, but I've been feeling pretty good. I'm going to try to keep it going."
Jeter got New York moving in the first inning against Buehrle, belting his 17th home run of the year to center field. The blast was the 223rd of Jeter's career, moving him past Don Mattingly for sole possession of 10th place on the Yankees' all-time list.
Damon touched Buehrle in the third inning for his 23rd homer, a shot into the first rows over the right-field wall at Yankee Stadium that leaves him one shy of his career high set in 2006.
That was all the Yanks got in six innings against Buehrle, who remained winless in seven starts since his July 23 perfect game over the Rays at U.S. Cellular Field.
After Sabathia exited with the no-decision, Phil Hughes struck out the side in a perfect eighth inning to lower his ERA to 1.23 as a reliever, and Mariano Rivera retired all three batters he faced in the ninth inning.
Brian Bruney then set down the White Sox in succession in the 10th inning, allowing Cano the opportunity to enjoy his second walk-off hit of the season, also having won a game on Aug. 12 against the Blue Jays in New York.
"We'd rather win them earlier than walk-offs," Bruney said. "That means we've been in a lot of close games. I think for the bullpen, that's beneficial.
"We're pitching in a lot of tight games like it's going to be in the playoffs. Fortunately, we're getting our reps in, but obviously we'd like to win those earlier in the game."