Shepard suffered a quad injury running a route late in the second quarter of New York's 20-17 loss. He immediately grabbed at his leg.
"It looked like he got twisted around by the defender on that penalty," Giants coach Joe Judge said. "I only saw a brief replay of it out of the corner of my eye so I'm running on secondhand information. I don't have a final diagnosis on where he's at. Obviously, he wasn't able to come back into the game so we'll see where he's at. Hopefully it's not too bad."
Pettis injured his shoulder earlier in the half as he was trying to recover his own muffed punt.
The injuries left the Giants short on wide receivers. Kenny Golladay (knee) was already inactive Monday night and missed his third straight game. Rookie first-round pick Kadarius Toney (ankle) was playing, but he was used on a limited basis in the first half and later departed in the fourth quarter with a thumb injury. He said after the game that his thumb got stepped on but he "came back out there to fight with my teammates."
Asked about Toney's limited playing time, Judge responded, "I would not call it a pitch count, but we were structuring it based on how he did in practice this week. Things we're doing.
"We built him up as we were going through the games. He had the hand issue and then he was able to come back."
Shepard has had trouble staying healthy this season. He missed two games at the start of the year with a hamstring injury, then missed last week after tweaking his other hamstring.
Shepard had four catches for 25 yards before exiting on Monday night.
"It's tough because you want to go to war with your brothers," Toney said of seeing his teammates go down with injuries. "At the end of the day, if they aren't able to go, you still have to step up."