The Raptors won for the second time in three games after dropping four in a row and leaned heavily on DeRozan to pick up the victory.
DeRozan gave Toronto a 95-93 lead with 37 seconds to play by making a jumper, but Orlando tied it with 20 seconds left on E'Twaun Moore's layup following an offensive rebound.
The winning basket came as DeRozan was being heavily guarded by both Glen Davis and Aaron Afflalo.
DeRozan led the Raptors with 24 points and seven assists. He made 10-of-17 from the field as part of Toronto's 50 percent shooting performance. Amir Johnson added 21 points and 10 rebounds.
Nikola Vucevic scored 19 points to go with 14 points for Orlando, loser of four straight.
The late dramatics came after Toronto had let an 11-point lead get away in the fourth period.