Beckham appeared to suffer a gruesome left ankle injury during a 27-22 loss to the Chargers on Sunday.
As if the Giants season could not get any worse, the unthinkable happened. Injuries cost him five games during his first two years, but he was on the field for all 16 games in 2016.
With 40 seconds remaining and the offense completely shattered, Manning threw an interception sealing the loss and dropping the Giants to 0-5.
Through four games, Beckham had three touchdowns.
Earlier in the game both Marshall and Shepard left with ankle injuries on separate plays in the half and did not return. For a player who can be such a lightning rod for opinion, prayers and well-wishes is the consensus among Giants fans and NFL Twitter at large.
He tweeted: "Odell Beckham is headed for surgery, per source".
Late in the fourth quarter, Beckham went up for a catch, was hit in the air by a Los Angeles Chargers defender, and came down under the defender, his ankle bending underneath the defender's body.