Manning opened the game by leading the Broncos on an 80-yard touchdown drive - their first opening-quarter touchdown of the season - and Denver never trailed.
The Broncos (2-2) beat the Raiders (1-3) at home for the first time since 2007.
Willis McGahee ran for 112 yards for his 32nd-career 100-yard game.
The Broncos held Darren McFadden to 34 yards on 13 carries and Carson Palmer, who led Oakland to a comeback win last week over Pittsburgh, never got on track. He finished 19 for 34 for 202 yards.
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