Peppers ruptured the ACL in his right knee in the third quarter of the 25-3 victory. He also suffered a high ankle sprain and was placed on injured reserve.
He's now the third Giants captain to land on season-ending injured reserve this season, joining offensive lineman Nick Gates and middle linebacker Blake Martinez. Another captain, running back Saquon Barkley, has also missed a pair of games as the team has been ravaged by injuries in recent weeks.
It's a tough way for Peppers' career with the Giants to perhaps end. Peppers was playing this season on the fifth-year option to his rookie contract. He is a free agent at the end of the season.
"I know the game means a lot to Pep," coach Joe Judge said on Monday. "He's a tremendous leader on this team and brings a lot to us in terms of production and just leadership on the field."
Peppers, 26, had 30 tackles and a sack this year. He missed a pair of games because of a hamstring injury and had seen his playing time and role decrease this season. He had fallen behind veteran Logan Ryan and second-year player Xavier McKinney in the safety rotation.
The Giants acquired Peppers along with first- and third-round picks back in 2019 in the trade that sent wide receiver Odell Beckham Jr. to the Cleveland Browns. But his time with the Giants has been marred by a variety of injuries, tallying 17 missed games in three years.
Peppers, a New Jersey native, was a first-round pick in the 2017 NFL draft out of the University of Michigan.
In a flurry of other roster moves, the Giants are signing defensive back J.R. Reed off the Los Angeles Rams' practice squad and waiving wide receiver David Sills and cornerback Josh Jackson from the active roster.
Defensive tackle Woodrow Hamilton was also released off the practice squad.