In addition, starting right guard Dan Connolly (concussion), outside linebacker Jermaine Cunningham (calf) and defensive linemen Mike Wright (concussion), Myron Pryor (back) and Brandon Deaderick (shoulder) have been ruled out.
That's a significant list of some key players for the Patriots, who can clinch the AFC East and the top seed in the conference with a victory.
Without Hernandez, the Patriots will have just two tight ends active against the Bills (Rob Gronkowski and Alge Crumpler). That could lead to some more pure three wide receiver packages with Brandon Tate and possibly Julian Edelman.
With Wright, Pryor and Deaderick out on the defensive line, the Patriots will likely have Landon Cohen active as sub rusher. The lack of depth also makes Ron Brace's status crucial. He is questionable with a concussion.
And with Cunningham out, the Patriots lose their starting outside linebacker in the 3-4 alignment. Tully Banta-Cain, if healthy, will probably step in.
The Patriots will have to downgrade two more players 90 minutes before the 1 p.m. ET kickoff.
Mike Reiss covers the Patriots for ESPNBoston.com.