The Twins took another step toward the American League Central title, moving eight games in front of the second-place White Sox and reducing their magic number for clinching the crown to 10.
Minnesota has defeated Chicago in 12 of their 17 meetings this season, including nine of the last 11. The Twins have 11 victories in their 13 September games.
Mauer's homer started a streak of three straight three-run innings for the Twins.
A sacrifice fly and two infield singles delivered Minnesota's sixth-inning runs and Jim Thome highlighted the seventh with a two-run single.
Brian Duensing (9-2) allowed two runs on nine hits in six innings to pick up the victory.
Gavin Floyd (10-13) was roughed up for six runs on nine hits in 5 1/3 innings. He is 0-4 against the Twins this season with an 8.06 ERA.
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