After scoring 15 runs against the Yankees in their first two games this year, the Red Sox were slowed down by the 40-year-old Pettitte. He scattered eight hits and walked one.
The Yankees scored three runs over the first three innings and then turned things over to the veterans Pettitte and Mariano Rivera.
Rivera put two on with one out in the ninth, but eventually picked up a shaky save in his first appearance of the season. He has said this will be his last year after having undergone knee surgery in 2012.
The only Boston run off Pettitte came on Francisco Cervelli's homer in the seventh.
Ryan Dempster suffered the loss in a five-inning stint. He allowed three runs on five hits and four walks while striking out eight.