It is unclear when Shepard was injured. He had six catches on seven targets for 42 yards in a 35-17 season-opening loss to the Dallas Cowboys this past Sunday.
Shepard finished the game without any noticeable incident. He was on the field for 68 of 69 offensive snaps -- most among Giants receivers.
Coach Pat Shurmur said Monday afternoon that Shepard was undergoing tests and might be dealing with a concussion.
"Yeah, he's getting tested," Shurmur said. "He has to go through some of the testing. It appears like he might be in the protocol here. But each guy is different, as you know. We'll just have to see how it goes here."
Shepard landed in the concussion protocol later in the day.
The fourth-year receiver's presence is vital given the current state of the Giants' receiving corps. Golden Tate is currently serving a four-game suspension for violating the league's policy on performance-enhancing substances, and Odell Beckham Jr. was traded in the offseason.
Shepard is expected to serve as the Giants' unquestioned No. 1 receiver early this season. The Giants don't have another option on the roster who has accumulated more than 1,000 career receiving yards.
"Hopefully, we get [Sterling Shepard] back," quarterback Eli Manning said. "If not, Russell Shepard is a guy that's been in the offense and played well and done some good things for us. He'll have to step in, and so hopefully we can get Sterling back for this week."
The Giants will have their work cut out for them with their passing game this week. The Bills allowed the second-fewest passing yards in Week 1 entering Monday night (155 yards) and had the best pass defense in the NFL last season.
Shepard is the most accomplished receiver on the Giants' active roster. He had 66 catches for 872 yards last season.