George Hill provided a three-point play with 46.5 seconds left to give the Pacers their first lead at 93-92 following a 17-0 fourth-quarter run.
After Kyrie Irving's free throws put the Cavaliers back on top, George sank the decisive shot from left corner for a 96-94 Indiana advantage.
The Pacers then went on to close out the win, outscoring Cleveland 35-10 in the final frame.
Hill ended with 29 points for Indiana, which holds the third seed in the Eastern Conference.
Irving topped the Cavaliers with 29 points and seven assists.