But starts like this will force readjusting of the landscape. Hughes was hit for five runs on six hits, lifted in the fourth inning after completing at least five frames in each of his previous 23 starts.
"It can't happen, especially when we're trying to win a series here," said Hughes, who tied a season high with five walks. "My pitch count was out of control and I wasn't able to get that big strike when I needed it. It seemed like I was just missing, and that was kind of the theme of the night."
With the Rays' afternoon loss to the Angels in Anaheim, New York remained tied for first place in the American League East.
The Blue Jays got on the board quickly against Hughes, as Wells ripped a RBI triple to right-center in the first inning and came home on a passed ball strike that ticked off of catcher Jorge Posada's glove.
"It was a cutter that backed up," Hughes said. "It kind of acted like a changeup. That's why [Adam] Lind swung and missed. Sado was looking for a pitch inside and it was way outside."
Wells clubbed his 23rd homer in the third inning, a two-run blast with Jose Bautista aboard that made it 4-2 at the time.
"They hit home runs," Yankees manager Joe Girardi said. "You've got to make pitches on them. It's like a lot of American League lineups -- if you don't make pitches, they can hurt you."
Fighting poor command of his fastball, Hughes was on the brink of escaping a bases-loaded jam in the fourth, when Robinson Cano made a slick stab up the middle on a Wells bouncer.
But Cano had to flip the ball softly to Derek Jeter, who was a step slow covering second base. Umpire Jerry Meals called the sliding Bautista safe, allowing Aaron Hill to score the fifth Toronto run as Hughes barked toward the play.
"I was a little frustrated," Hughes said. "Vernon Wells hits a rocket and Robbie is right there. We just need that out to get out of the inning. It's one of those plays where your emotions just take over."
Maybe Hughes had a point -- after Meals' call, Jeter made sure the play was dead and then walked back to voice his own opinion. Girardi raced from the first-base dugout, protesting a little more emphatically.
"It was a bang-bang play and I never saw a replay," Girardi said. "When Jeet says something, it makes me feel that maybe he's out. They said it was really close."
With Hughes done after 102 pitches, the Yankees called upon Javier Vazquez in relief. The veteran was skipped for an upcoming start Sunday in favor of rookie Ivan Nova, who pitched the series opener at Toronto on Monday.
Vazquez served up Hill's 19th homer in the fifth, a solo shot to left field that snapped an 0-for-20 skid, but then settled in and was able to keep the Blue Jays in check with 4 1/3 two-hit frames.
"I felt good," Vazquez said. "I was aggressive, threw strikes, didn't try to be too fine. Coming from the 'pen, it does feel different. Obviously I've been a starter my whole life. ... I got it done today."
"He was great," Girardi said. "He gave us an opportunity to come back and win this game. We just didn't score any runs."
The Yankees managed to push just two across in eight innings facing left-hander Brett Cecil, with both coming on Marcus Thames' long two-run homer -- his sixth -- in the fourth inning, as Thames homered in back-to-back games for the first time this season.
New York also had a prime opportunity when Thames stroked a one-out double in the second, but Cecil worked into and out of trouble, leaving the bases loaded by getting Eduardo Nunez to hit into an inning-ending groundout.
The Bombers had their last chance in the ninth, as Cecil's work was complete, improving to 7-1 with a 2.14 ERA in nine starts this year against the AL East, including 2-0 with a 1.64 ERA in three starts vs. New York.
To get there, Jason Frasor had to protect a four-run lead, but lost Austin Kearns and Brett Gardner to a pair of two-out walks.
Nunez greeted closer Kevin Gregg by drawing the Yankees within three runs, stroking an RBI single to center, and Jeter was hit by a pitch to load the bases and put the go-ahead run at the plate.
But Gregg got Curtis Granderson to fly out to center field to end the game, securing his 29th save in 33 chances and two wins in three games for the Blue Jays, who see the Yankees six more times and seem to be relishing their role as a potential playoff spoiler.
"They can hit," Hughes said. "That's kind of their M.O. They look for a good pitch to hit, they swing hard and they don't get cheated. We're going to have to come back and play these guys tough, because they're not backing off at all."