The 27-year-old left the Giants' Week 2 loss to the Chicago Bears with the toe injury.
As a rookie in 2016 and in 2018, Shepard appeared in all 16 games and was a crucial piece of the Giants' receiving corps. Two years ago he caught 66 of 107 targets for a career-high 872 yards and four touchdowns, and last year the Oklahoma product collected 576 yards on 57 catches with three touchdowns.
In Week 1, Shepard caught six passes for 47 yards as the Giants fell to the Pittsburgh Steelers.
With Shepard out, the Giants will likely rely on Evan Engram, Darius Slayton and Golden Tate, who missed Week 1 with a hamstring issue and got called for pass interference with four seconds left to play as the Giants tried to come from behind in Week 2.