Instead of going with his fastball one more time, the right-hander threw a looping curve that dropped Reyes to a knee as he swung through it for strike three.
Hughes made another lead hold up for his 10th victory this season and the Yankees ended the New York Mets' eight-game winning streak, 5-3 Saturday.
"I needed to find something right there to get him out," Hughes said. "He had done a lot of damage. I just needed to execute that pitch and fortunately I was able to do it."
Reyes had homered in his first two at-bats, but Mark Teixeira and Curtis Granderson each hit a two-run homer to give Hughes a lead in his matchup against another rising star, Mike Pelfrey, after four innings.
And when given the lead, Hughes (10-1) protects it.
In 12 of his 13 starts, the 23-year-old right-hander has not allowed an opponent to tie or take the lead once the Yankees are ahead. The only time his teammates failed to give him the lead was against the Mets and Pelfrey (9-2) on May 22, his only loss.
"When you have a lead, you can be more aggressive and do some of the things you want to do," Hughes said.
Yankees manager Joe Girardi attributes Hughes' success this year to the 44 appearances he made out of the bullpen last season.
"He pitched in those tough games all last year for us when there was never a lot of room for error," Girardi said. "He seemed to always find a way to get it done. He was outstanding last year out of the bullpen and he's just carried it right over to the rotation."
Hughes said that time in the 'pen gave him the confidence to succeed as a starter.
The win ended the Yankees' three-game skid and tied Hughes with another budding star, Tampa Bay's David Price, who is 10-2, for the AL lead in wins. Hughes allowed five hits and three walks in seven innings. He struck out four and threw a wild pitch.
Joba Chamberlain pitched a scoreless eighth, rebounding from a poor performance against the Phillies on Thursday night in which he gave up three runs without getting an out.
Mariano Rivera worked a perfect ninth for his 16th save in 17 chances.
The Yankees scored more runs Saturday than they had in their past three games overall (four) -- without the help of shortstop Derek Jeter, who was a late scratch from the lineup because of a bruised right heel. He was hurt running to first Friday night in a 4-0 loss to the Mets.
Girardi said Jeter was sore and he'll be evaluated Sunday before a decision is made on whether he'll play in the series finale.
The Yankees can even the 2010 Subway Series at 3-all Sunday, when they send CC Sabathia to the mound against Johan Santana in a pairing of former Cy Young Award winners. The Mets took two of three from their crosstown rivals at Citi Field in May, with Santana beating Sabathia in that series finale.
Reyes homered on the game's second pitch but the Yankees answered in the bottom half on a double-play grounder by Teixeira to tie it.
Reyes connected in the third after Hughes walked No. 9 batter Henry Blanco for his sixth multihomer game. The ball just cleared the right-field wall several yards from where his first drive went out. Nick Swisher leaped but did not get his glove over the top of the wall.
"Some stadiums you feel comfortable hitting. I feel comfortable here," Reyes said. "I was seeing the ball really well."
Teixeira tied it with a two-run drive an out after Brett Gardner got his second single to start the bottom of the inning, and Granderson hit a long homer to right after Pelfrey walked Posada leading off the fourth for a 5-3 margin.
Pelfrey let the leadoff batter reach in five of his seven innings. He gave up five runs, the most he's allowed since giving up six to the Phillies on May 1, which ended the Mets' other eight-game winning streak this season.
"I didn't have a fastball today. I ended up getting behind guys," Pelfrey said. "They gave me a lead. I just couldn't hold it. We're playing well. I just feel bad."
The Mets' 4-0 win Friday night took 3 hours, 41 minutes. Saturday's game lasted 2 hours, 39 minutes. ... Mets manager Jerry Manuel said RHP John Maine (sore shoulder) will need at least one more rehab start before being activated from the disabled list. ... Yankees RHP A.J. Burnett reported no problems with his bruised foot after his bullpen session and said he would be able to make his next scheduled start Monday night in Arizona. ... The matchup between Pelfrey and Hughes was only the second time two starters had at least nine wins and a winning percentage of .900 or higher, according to the Elias Sports Bureau. The other time was in 1900.