Manning completed 30-of-38 passes for 338 yards in his fourth game since coming to the Broncos as a free agent in the off-season, sparking Denver to 27 unanswered points.
Star running back Darren McFadden was limited to 34 yards on 13 carries for Oakland (1-3).
Carson Palmer passed for 202 yards on 19-of-34 efficiency in the loss.
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