Cano homered on each of his first two swings against the two-time Cy Young Award winner and the New York Yankees hit four long balls off an ineffective Santana in a 9-1 rout of the Mets on Friday night.
Cano's second shot was the first of three straight homers off Santana, who was coming off a no-hitter against St. Louis.
"That's a guy you want to go and be aggressive because you don't want to get behind the count," Cano said. "He's got some great pitches."
In the first Subway Series game of the season, Hiroki Kuroda allowed one hit in seven scoreless innings before leaving with a bruised left foot. Kuroda (5-6) gave up only a two-out double in the sixth to Omar Quintanilla but ended the night hopping out of the clubhouse on crutches.
Kuroda's first appearance in the crosstown rivalry was cut short when Daniel Murphy scorched a liner off the pitcher's foot, eliciting "oohs" from the crowd of 48,566 -- just the second sellout at Yankee Stadium this season. The ball popped up high and was caught by third baseman Alex Rodriguez for the final out of the seventh.
Kuroda limped off the field and down into the clubhouse, followed by several teammates and trainers. Yankees manager Joe Girardi wasn't sure whether Kuroda will make his next start.
"I think any time you get hit in the foot like that you have to be somewhat concerned," Girardi said.
Santana (3-3) was given two extra days of rest after throwing a career-high 134 pitches last Friday in the first no-hitter in Mets history. But he didn't have it this time, serving up a career-high four homers during New York's fourth loss in five games
"A couple of extra days and I felt fine," Santana said. "I just didn't have my feeling for a couple of my pitches. There were times when they stayed up and when you leave pitches up, you know, they're a pretty good team and in this ballpark, you keep pitches up, they end up out of the park, and that's what happened."
Mets manager Terry Collins had a different take on Santana's performance. He blamed himself, saying the two extra days between starts left Santana rusty.
"It's my doing, it's not his," Collins said. "We erred on the side of caution and it cost us the game tonight."
Santana is 0-3 with a 12.21 ERA in three starts at the new Yankee Stadium. The Mets fell to 35-50 against their crosstown rivals during the regular season.
After a perfect first inning, Santana walked Rodriguez to start the second, his last two pitches missing badly. Cano lined the next pitch into the right-field seats for the first runs off Santana since May 21, three starts ago. He had a scoreless streak of 19 innings.
Rodriguez singled with two outs in the third. Cano then set off a barrage of long balls in an 11-pitch span with a drive into the second deck in right, again on a first pitch, for his eighth multihomer game.
Cano had two tries for a third homer but popped out and grounded out.
There was no need to worry about a pitch count for Santana. He was lifted after five innings, having allowed six runs and seven hits. He threw 86 pitches.
Kuroda had a poor history against the Mets, going 1-5 with a 5.75 ERA against them with the Los Angeles Dodgers.
This time he had the Mets flailing at a slider that fooled lefties and righties. There wasn't a hard-hit ball until Quintanilla's double. The most difficult play until then came after Josh Thole reached on Derek Jeter's error at shortstop. David Wright broke his bat near the handle, sending much of it spiraling toward Rodriguez, while hitting a grounder to third. A-Rod calmly fielded the ball and started a double play as the bat soared over his head.
As Kuroda worked his way through the Mets' lineup, Girardi started thinking the right-hander might be able to give New York a no-hitter for a second straight Friday.
"With what Santana did last week you kind of thought, maybe this could happen here," Girardi said.
Kuroda has made three solid starts in a row, giving up just two runs in 22 innings. This time he struck out seven and walked one.
Swisher had an RBI double and Jones a run-scoring single in a three-run seventh.
Jason Bay went 0 for 3 in his return to the Mets' lineup. He had not played since April 23 because of a broken rib. ... The previous time the Yankees hit back-to-back-to-back homers was Aug. 28 at Baltimore. ... Yankees reliever Joba Chamberlain threw off a mound for the first time since hurting his ankle jumping on a trampoline in March. Chamberlain made 25 throws in a batting cage at the team's minor league complex in Tampa, Fla. Chamberlain, also coming off Tommy John surgery, has no doubt he will pitch this season. "Is that even a question?" he said.