Hughes held Baltimore without an earned run over eight innings, Joe Mauer had four RBIs and the Twins won 6-4 Monday to avoid a four-game sweep.
After being outscored 24-11 in the first three games of the series, Minnesota won for only the second time in nine tries.
Hughes (15-9) gave up five hits, no walks and three unearned runs. The right-hander has allowed one earned run or fewer in five of his last six starts.
"He's been huge," Mauer said. "Whenever we give him the ball, we feel like we have a real good chance of winning."
Following a 4-14 season with the Yankees last year, Hughes has accounted for 25 percent of Minnesota's 60 wins.
"I feel like I got away with a lot of mistakes today," the right-hander said. "But I had good enough stuff to overcome that and was able to make some pitches. That was kind of the story."
Mauer tripled in two runs in the sixth inning and added a two-run single in the eighth to put Minnesota ahead for good. The victory provided the last-place Twins with reason to believe they can put a positive finish on a miserable season.
"We're 1-0 in September and we need Joe to pick us up," manager Ron Gardenhire said. "Let's have a good September here. That's kind of our battle cry, and it's going to be led by him, no doubt."
Hughes should play a part, too.
"He's had a solid year for them," Orioles manager Buck Showalter said. "He's always taking the ball, giving innings. He's a good addition."
After Hughes left, Glen Perkins gave up a leadoff homer to Cruz in the ninth before getting three straight outs for his 33rd save.
Hughes and Orioles rookie Kevin Gausman (7-7) matched zeroes until the sixth inning, when the Twins took a 3-0 lead.
Danny Santana and Brian Dozier hit one-out singles before Mauer hit an opposite-field liner to left that bounced off the wall toward center. Mauer ended up with his second triple of the season, and Kennys Vargas followed with a sacrifice fly.
In the seventh, a single and a throwing error by third baseman Trevor Plouffe preceded Hundley's two-out drive into the left-field seats.
The deadlock didn't last long. Gausman gave up a leadoff walk in the eighth, and an error by third baseman Jimmy Paredes put runners on second and third with no outs. Mauer singled off Andrew Miller, took second on the throw to the plate and scored on a single by Vargas.
"It kind of (stinks) that I walked the leadoff guy in the eighth inning," Gausman said. "That kind of came back to bite us."
Gausman allowed five hits and four earned runs in a career-high 7 1/3 innings, losing his third straight start.
"I thought I threw the ball where I wanted to," he said. "A lot of their hitters are down hitters, so I think fastball up was a big pitch for me today. I used it effectively. I mixed in all my pitches."
Twins: C Kurt Suzuki, who sat out Sunday's game after taking a foul tip in the chin on Saturday night, returned to the starting lineup.
Orioles: 1B Steve Pearce missed a third straight game with an abdominal strain, but Showalter said Pearce is improving and should be back in a day or two. Also, SS J.J. Hardy was pulled after the seventh inning with back spasms.
"I sure hope I'll be in there (Tuesday)," he said. "I think getting out of there today was probably the right decision."
Twins: The Twins return home to face the White Sox on Tuesday night. Minnesota starter Tommy Milone is 1-0 with an 0.86 ERA against Chicago.
Orioles: Baltimore opens a three-game interleague series against visiting Cincinnati. The Orioles haven't lost two in a row at home since June 28-29.