Manning went 22-of-35 passing for 259 yards with two interceptions. Wilson recorded three touchdowns -- including a 97-yard kickoff return.
Victor Cruz hauled down eight passes for 121 yards and a touchdown for the Giants (8-5), who scored their most points in a game since 1986 while maintaining their grip on first place in the NFC East.
The fading Saints (5-8), meanwhile, lost for the third straight week despite 354 passing yards and a touchdown from Drew Brees.
The New Orleans signal-caller completed 26-of-43 passes but was intercepted twice.
Darren Sproles caught a TD pass and also scored on the ground for the Saints.