He was an All-American college football player at the University of Michigan, and was selected by the New York Giants in the third round of the 2008 NFL draft.

Manningham won Super Bowl XLVI with the Giants, defeating the New England Patriots, and catching a crucial 38-yard pass in the final minutes.

[3] Manningham made his first game appearance after the injury as a reserve wide receiver on November 4 against Ball State.

[6] Manningham had reportedly been removed from "multiple teams'" draft boards due to alleged marijuana use in college.

[11][12] During rookie training camp, Manningham noted that he looked forward to playing with fellow former Michigan Wolverine Amani Toomer.

[15] Manningham kicked off the 2009 season by catching three passes for 58 yards and a touchdown en route to the Giants' 23–17 win over the Washington Redskins.

[19] In the Giants' final game of the 2010 regular season, he recorded four receptions for 101 yards and a touchdown in a 17–14 win over the Washington Redskins.

[22] On February 5, 2012, Manningham made a catch in the fourth quarter of Super Bowl XLVI to set up the win against the New England Patriots.

Eli Manning lofted a long pass down the left sideline to Manningham, who kept his feet in-bounds by a fraction of an inch with two defenders around him for a gain of 38 yards.

[25] On December 23, 2012, he tore his ACL and PCL in his left knee against division rival, the Seattle Seahawks, in a game the 49ers lost 42–13.