Manning connected on 25 of his 42 pass attempts for 270 yards with an interception for the AFC West-leading Broncos (7-3), who won their fifth straight.
Brandon Stokley hauled down a scoring pass among his four grabs for 55 yards, while Eric Decker and Demaryius Thomas also were on the receiving end of Manning TD passes for Denver.
The reeling Chargers (4-6), meanwhile, lost for the fifth time in six outings as Phillip Rivers was intercepted twice.
The San Diego quarterback completed 24-of-40 passes for 258 yards and pair of scoring strikes to Danario Alexander.
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