Hughes, who could be the odd man out when Freddy Garcia returns on Saturday, has won his last two starts, but is just 3-4 on the year with a 6.55 earned run average. He beat the Tampa Bay Rays on Saturday by holding them to a pair of runs and four hits in six innings.
"It's hard enough to pitch a really good game when you have a clear conscience so I knew I couldn't let anything distract me," Hughes said.
He is 3-3 with a 4.28 ERA in seven games since returning from the disabled list in early July.
Hughes has faced the Twins three times (one start) and has yet to record a decision against them, pitching to a 3.68 ERA in those outings.
New York opened this set with a win on Thursday, as Mark Teixeira finished 2- for-3 with a two-run homer, two runs scored and two walks, carrying the Yankees to an 8-4 win.
Nick Swisher added a two-run shot and Andruw Jones hit a mammoth solo blast for New York, which won for the sixth time in eight games to stay atop the AL East standings by a half-game over Boston.
CC Sabathia (17-7) struck out nine in seven innings and survived 10 hits and four runs -- three earned -- to end a two-start skid.
Brian Duensing (8-12) surrendered 10 hits -- three homers -- and six runs over five innings to drop his fourth straight start.
Minnesota nearly began its 11-game homestand with a two-run lead in its first at-bat, but instant replay overturned Justin Morneau's home run down the right-field line. The reversal came a day after the Yankees had a home run hit against them incorrectly upheld by replay in a 5-4 loss to the Royals.
Tonight, the Twins will rely on righty Kevin Slowey, who will be making his first start of the season. Slowey was a 13-game winner last season, but has made just six relief appearances this season due to numerous injuries.
Slowey actually started Sunday's tilt with the Cleveland Indians, but that game was washed out by rain after two innings.
"I felt good," said Slowey, who has pitched to a 4.91 ERA this season. "But it was only a couple innings. The only thing [catcher Drew Butera] and I could really tell was that [the Indians] were out there swinging from the get-go. Again, two innings, there's really not much to glean from that."
He is 1-1 with a 4.56 ERA in five games (four starts) against the Yankees.
The Yanks took two of three from the Twins earlier in the year and have won six of their last seven in Minnesota.