Mauer entered the game in an 0-for-10 skid, but had an RBI single in Minnesota's four-run first inning. He also singled in the second and hit a two-run homer in the seventh off Tony Sipp.
Trevor Plouffe's one-out homer in the sixth off Josh Tomlin (2-3) broke a 4-all tie.
Brian Duensing (1-2) pitched two scoreless innings as the Twins won for the fourth time in five games. Matt Capps pitched the ninth for his 11th save.
The Indians have lost six of eight, due primarily to poor starting pitching. Cleveland's starters are 2-6 with a 9.52 ERA in the last eight games.
Mauer was behind the plate Saturday for the first time since being hit in the face mask with a foul tip Monday.
Minnesota sent nine men to the plate in the first off Tomlin, who needed 32 pitches to get through the inning. Mauer and Justin Morneau had RBI singles and Plouffe added a two-run single with the bases loaded.
Twins starterP.J. Walterscouldn't hold the lead and didn't get through the fifth inning. The right-hander allowed four runs in 4 innings.
The Twins announced before the game pitcher Carl Pavano will return to Minneapolis on Sunday to have an MRI on his sore right shoulder. Pavano is 2-5 with a 6.00 ERA in 11 starts. He's scheduled to start Wednesday against Kansas City.