The 41-year-old left-hander picked up strikeout No. 2,000 when he got Red Sox catcher David Ross to swing through an 85 mph slider to end the top of the fourth inning.
Pettitte is the franchise's all-time leader in strikeouts. Whitey Ford (1,957) is second and Ron Guidry (1,778) is third.
Pettitte came into the game with 1,993 career K's as a Yankee.