The Redskins led by three and had the Giants pinned on their own 23-yard line, but Manning floated a perfect pass for Cruz and the wideout outsprinted four defenders to the endzone as the hosts claimed a 27-23 win.
The winning score came just 19 seconds after Robert Griffin III connected with veteran Santana Moss for a 30-yard score which looked to have bagged victory for the Redskins.
Moss had earlier scored on a 26-yard pass from Griffin after Andre Brown had powered over from a yard out in the second quarter, while Kai Forbath and Lawrence Tynes both nailed a pair of field goals each.
The score remained 13-13 after a blank third quarter, but the Giants reclaimed the lead when Ahmad Bradshaw burrowed over from the one-yard line.
Forbath replied with his third field goal, and Griffin then engineered a 77-yard drive on seven plays that resulted in a second score for Moss.
But Manning, who three for 337 yards, and Cruz had the final word as the Giants moved to 5-2 for the season to open up a two-game lead over Philadelphia and Dallas in the NFC East.