Lowry returned from a seven-game absence brought on by a slight tear in an arm muscle and he came through in the extra period to bring the Raptors their sixth win in seven games.
He made a reverse layup 2 minutes into overtime to give Toronto a four-point lead and he then hit a 3-pointer for a 98-93 advantage.
DeMar DeRozan scored 30 points for Toronto, which won on the road for just the third time this season. Lowry finished with 17 points and eight assists.
DeRozan hit two free throws with 14 seconds left in the fourth period to give Toronto a three-point lead, but Ryan Anderson converted a 3-pointer for New Orleans with 8 seconds remaining to force overtime.
New Orleans was paced by 20 points, 14 assists and nine rebounds by Greivis Vasquez, but the Hornets lost for the 12th time in 13 games. They ended an 11-game losing streak on Wednesday against Orlando.