Manningham did not travel with the team on Saturday to Philadelphia and was downgraded from doubtful to out.
Manningham suffered a concussion in the first half against the Rams on Monday night. He was held out of practice all week long and was considered a long shot to play against the Eagles.
Eli Manning faceed Philadelphia's vaunted secondary -- featuring Nnamdi Asomugha, Asante Samuel and Dominique Rodgers-Cromartie -- without his second- and third-best receivers with Manningham sidelined by the concussion and Domenik Hixon out for the season with a torn anterior cruciate ligament.
The Giants were likely to start Victor Cruz at wide receiver opposite Hakeem Nicks with Manningham out. Cruz and Brandon Stokley also could see time in the slot with Devin Thomas perhaps seeing more snaps.
The Giants also signed Michael Clayton on Friday to provide depth and help on special teams.
Ohm Youngmisuk covers the Giants for ESPNNewYork.com.