Trevor Plouffe, Ryan Doumit and Pedro Florimon connected against Hughes -- all on 2-2 pitches with one out. Minnesota snapped a six-game losing streak with its second victory in 14 games, winning for the first time in six meetings with the Yankees this year.
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New York won 32 of the previous 39 matchups, including a pair of playoff sweeps.
"It's a big sigh of relief," Doumit said. "This has been a tough road trip, no doubt."
Beaten by Hughes earlier this month, Deduno (5-4) scattered six hits in his first start at Yankee Stadium. He struck out three, walked three and matched the longest outing of his career.
Casey Fien pitched a scoreless eighth -- with help from his shortstop. Florimon saved the reliever from a throwing error on a comebacker with nobody out.
All-Star closer Glen Perkins, making his first appearance in a week, got three outs for his 21st save in 23 chances.
"Exciting baseball game," said Twins manager Ron Gardenhire, ejected in the eighth for arguing a call at first base. "That was needed. It's been a tough go here to get a win, so to see the guys smile again is very exciting."
The Yankees, who swept four games in Minnesota from July 1-4, had won three straight and nine of 12.
Hughes (4-9) tied a career high with 10 strikeouts in 7 1/3 innings but gave up three homers in a game for the second time this season. He has allowed 18 long balls in as many starts.
"I thought it was some of the better stuff he's had all year," manager Joe Girardi said. "I think he threw the ball exceptionally well except for a few mistakes."
About 13 hours after the Yankees finished a rain-delayed shutout Friday night, the teams were back on the field.
New York jumped on top in the first inning when Ichiro Suzuki doubled and scored on Robinson Cano's single. Deduno got Vernon Wells to ground into an inning-ending double play and settled in from there.
The right-hander, who pitched the Dominican Republic to the World Baseball Classic championship in March, received some help when Doumit caught Zoilo Almonte stealing second with a runner on third to end the fourth. Deduno struck out Suzuki with two on to finish the fifth and worked around a one-out double in the seventh.
"Everything was around the plate and everything was working today," Deduno said.
Plouffe tied it in the second on a long drive to left-center and Doumit put the Twins ahead in the seventh with a line drive to right.
"That's a single at Target Field. It might be an L-9," Doumit said, referring to Minnesota's pitcher-friendly home. "This is a great place to hit."
Gardenhire was tossed by plate umpire Vic Carapazza in the eighth after Clete Thomas and was called out for interference when Hughes' throw to first hit him in the back and bounced away. Aaron Hicks, who opened the inning with a bunt single, was sent back to first base.
Florimon followed with his fifth home run, a high fly that cleared the short porch in right to make it 4-1.
"It's frustrating," Hughes said. "I've felt good with my stuff over the last three or four starts. There's just one or two mistakes that I have to stay away from. I have a straight fastball, a four-seamer, that when I miss over the plate with it, it leads to fly balls. I just have to concentrate on location, and it comes down to execution."
After the game, the Twins optioned RHP Michael Tonkin to Triple-A Rochester to make room for LHP Caleb Thielbar, who will be reinstated from the bereavement list Sunday. ... It was Gardenhire's 65th ejection as a manager and third this season. ... Rookie OF Oswaldo Arcia, who has struck out in 11 of his last 13 at-bats, was rested by the Twins. Arcia whiffed all four times up Friday night and is hitless in his last 20 at-bats. "He's swinging at some cartoon breaking balls. He's swinging three times at one pitch and he's not hitting any of them," said Gardenhire, who deemed it best to give Arcia a breather. "He's got the starry eyes right now. He's overwhelmed right now." ... Joe Mauer had two hits as the DH and Doumit started behind the plate. ... LHP CC Sabathia (9-7, 3.99 ERA) pitches New York's final game before the All-Star break Sunday against Twins RHP Kyle Gibson (1-2, 7.27), who will make his fourth big league start. Sabathia is 11-0 with a 2.01 ERA in his last 12 starts against Minnesota, including the postseason, since Aug. 3, 2007.
Copyright by STATS LLC and The Associated Press
NEW YORK, NY - JULY 13: Robinson Cano #24 of the New York Yankees connects on a first inning RBI base hit against...
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Home Plate - Vic Carapazza, First Base - Gary Cederstrom, Second Base - Kerwin Danley, Third Base - Lance Barksdale
Phil Hughes has 10 strikeouts through seven innings Saturday, tying his career high for strikeouts in a game (also had 10 on April 21, 2010).
Hughes also gave up three home runs Saturday, the 7th time in his career he's allowed three home runs in a game and 24th time he's allowed two or more home runs in a game, both of which are the most by any Yankees pitcher since the start of the 2007 season.