The Redskins had grabbed a 23-20 lead as time wound down as Robert Griffin III engineered a seven-play, 77-yard scoring drive, capped by a 30-yard TD pass to Santana Moss.
But Manning responded with a big play of his own, connecting with Cruz on a bomb down the middle for the decisive play.
Manning amassed 337 yards for the game, finishing 26-of-40 through the air with two interceptions as New York (5-2) notched a third straight victory.
Griffin finished with a pair of TDs and an interception on 20-of-28 passing, good for 258 yards for the Redskins (3-4).
Alfred Morris ran for 120 yards on 22 carries in the setback.
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