Shepard was not on the injury report all week until getting a questionable tag because of migraines on Saturday.
He was considered a game-time decision before being officially ruled out Sunday afternoon.
The Giants host the Kansas City Chiefs at 1 p.m. Sunday at MetLife Stadium. Cornerback Eli Apple, offensive lineman Justin Pugh, linebacker B.J. Goodson, quarterback Davis Webb, linebacker Kelvin Sheppard and tackle John Greco are also inactive for the matchup.
Shapard's departure is an immediate downgrade to Eli Manning's fantasy football value for Week 11. Shepard had his best game of the season in Week 10, going off for 142 yards on 11 catches. He has 475 yards and a touchdown on 38 receptions this season for the Giants.
Giants wide receivers Tavarres King and Roger Lewis get a slight upgrade as borderline WR3s in this great matchup. Tight end Evan Engram could have a big day as Manning's No. 1 option on Sunday. I expect a ton of looks for the rookie tight end here in a game where the Giants should trail. Engram is currently tied with Tennessee Titans veteran Delanie Walker for the most receiving targets for tight ends, with 72.