Thomas finished with seven catches for 108 yards, including three consecutive scoring grabs, to help Denver build a 28-6 lead in the third quarter.
Manning racked up 330 passing yards on 25-of-36 efficiency for the Broncos (8-1), who won in their first game under Del Rio. He is filling in while head Coach John Fox recovers from successful aortic heart valve replacement.
Manning was hurt after a low hit from defensive end Corey Liuget in the fourth quarter but stayed in the game.
Julius Thomas added a 74-yard reception for a score.
Philip Rivers compiled 218 passing yards with a touchdown for the Chargers (4-5).