Hughes will look to end a career-worst five-game home slide and outduel Samuel Deduno for the second time this month Saturday.
New York (51-42) is 9-8 in its last 17 games, with the majority of its victories in that span against Minnesota. The Yankees swept four on the road from the Twins (37-53) from July 1-4.
Hughes (4-8, 4.55 ERA) earned a 7-3 victory July 2 as he yielded one run over seven innings to improve to 4-1 with a 2.33 ERA in six career starts against Minnesota, including one playoff outing.
Deduno (4-4, 3.90) will oppose Hughes once again after giving up three runs in six innings in his second career start against the Yankees. He exited the first one Sept. 26 after recording five outs due to irritation in his left eye.
Hughes, meanwhile, has posted an 8.22 ERA in losing his last five starts in the Bronx. He gave up two runs over four innings Monday in an outing cut short by a rain delay - a 5-1 home defeat to Kansas City.
The right-hander, who went 11-4 with a 3.74 ERA at home in 2012, has fared well against Twins stars Joe Mauer and Justin Morneau. Including the postseason, Mauer is 5 for 20 against him and Morneau 2 for 13.
Deduno is 1-3 with a 5.40 ERA in five road outings compared to 3-1 with a 2.33 mark at home. The right-hander seeks to avoid losing three straight starts for the first time after giving up five runs and a season-high 10 hits over six-plus innings Monday in a 7-4 loss at Tampa Bay.
Minnesota fell to 7-31 at New York since 2002 with a 2-0 loss Friday to open this three-game set.
The punchless Twins have dropped six straight and 12 of 13, and are averaging 3.0 runs in July for the AL's worst mark. They were hitless in 12 at-bats with runners in scoring position Friday.
"We had opportunities and we put men out there just didn't come up with any big hits again, kinda what our storyline's been," manager Ron Gardenhire said. "Get them out there and missed opportunities.''
Robinson Cano had an RBI single in a two-run fifth inning. He's 8 for 17 with three homers and 10 RBIs in the season series and 1 for 4 in his career against Deduno - his teammate with the title-winning Dominican Republic at the World Baseball Classic this year.
Mauer and Morneau have done minimal damage by combining for five RBIs in the five meetings.
The injury-plagued Yankees decided Friday that Derek Jeter would not play the rest of the weekend after the shortstop strained his right quadriceps in his third at-bat Thursday in his season debut.
New York has also played its last two games without Travis Hafner, who is out with a left foot contusion although there's a chance he could see action Saturday.
"This group has been pretty good about moving on,'' manager Joe Girardi said.