The star quarterback completed 25 of 35 passes for 286 yards and three touchdowns at Sports Authority Field at Mile High.
Manning's combination with Emmanuel Sanders proved to be the key as the wide receiver caught three touchdown passes.
Chargers quarterback Philip Rivers had three touchdown passes and completed 30 of 41 for 252 yards but he was intercepted twice.
It saw the AFC West-leading Broncos - who lost last season's Super Bowl - improve to a 6-1 win-loss record this campaign, while the Chargers (5-3) slipped further behind in the division.
After a scoreless first quarter, Manning and Sanders put the Broncos in a winning position.
Sanders caught a two-yard touchdown pass but the Chargers responded as Rivers found Keenan Allen to level the scores.
But Manning and Sanders combined thanks to the former's 31-yard touchdown pass and they did so again early in the third quarter.
Juwan Thompson's rushing TD, the first of two, had the Broncos in complete control before Antonio Gates had two touchdown catches for the visitors.
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