OBJ was then taken off the field on a cart and footage captured the 24-year-old in tears with a towel over his face. It was the same ankle he injured in the preseason against the Cleveland Browns which caused him to miss Week 1.
That gave Los Angeles its first win against four losses, and dropped the Giants to 0-5.
Five plays earlier, Shepard hopped off the field with an ankle injury and collapsed on the sideline before getting evaluated and ruled out the remainder of the game.
Beckham had five catches for 95 yards and a touchdown before he was hurt.
The Giants' playoff hopes were probably gone before kickoff, but any extended absence of Marshall and Shepard would put whatever little optimism remained concerning the season's remainder to rest.