Pettitte (5-3) scattered seven hits and struck out three in the victory, which bumped up New York's lead in the AL East to 1 1/2 games over Baltimore.
Pettitte had offensive support in the form of four home runs. Nick Swisher, Curtis Granderson, Eric Chavez and Raul Ibanez all knocked it into the seats at Target Field. Swisher's two-run homer came in the three-run New York first inning.
Liam Hendricks (1-8) was roughed up in his 6 1/3-inning start and was tagged with the loss. Hendricks allowed six runs on eight hits.
Chris Parmelee drove in two runs for Minnesota with a two-out pinch-hit triple in the bottom of the ninth.
The Twins had won back-to-back games heading into Monday's opener of a three-game series with the Yanks.