Minnesota got two-run homers from both Jason Kubel and Luis Rodriguez, with Kubel's sixth homer this season breaking a 2-2 tie in the top of the seventh. Rodriguez's homer in the ninth was his second round-tripper this season.
Santana (10-6) walked two batters and fanned five.
New York's Hideki Matsui hit a solo home run in the second and Andy Phillips hit an RBI single in the fourth. Derek Jeter and Melky Cabrera had the other hits for the Yankees, who have split their last four games.
Loser Mike Mussina (4-6) gave up four runs -- three earned -- and five hits in six innings.