The key shot was the eighth trey of the contest for Lillard, who hit a game-winning basket for the fourth time this season. He finished with 36 points, 10 assists and eight rebounds.
The Blazers needed Lillard's late-game heroics after blowing a 10-point lead down the stretch, led by a late surge by Cleveland's Kyrie Irving.
The victory was the fifth straight and ninth in 10 games for Portland.
On the decisive play, Lillard held the ball until less than a second remained and hit the shot over the Cavaliers' Alonzo Gee.
Irving (25 points, 10 assists) missed a on desperation try to end the game as the Cavs had their four-game home winning streak snapped.