Mayo, a captain and signal-caller on defense, was immediately surrounded by teammates after a Boobie Dixon run up the middle on first down, as he wound up on the bottom of the pile. Patriots coach Bill Belichick also came over from the sideline, reflecting the initial reaction that the injury was serious.
The Patriots also lost running back Stevan Ridley to a knee injury and guard Dan Connolly to a head injury. Mayo and Ridley were scheduled to have MRIs Monday to determine the severity of their injuries.
Several Patriots and Bills players came over to the cart as Mayo was helped on, with Patriots veteran Vince Wilfork bringing Mayo's head into his own chest and kissing him on top of the head.
Mayo was seen walking with the aid of crutches and with a compression sleeve over his right knee after the game.
"I'm still a bit bittersweet with Jerod going down," Belichick told reporters after the game. "So we hope he's OK.
"We will just go forward this week and see what we think the best thing to do is."
Belichick was asked on his Monday conference call about how the team can move on if Mayo's injury causes him to miss significant time.
"Well, it already happened yesterday," Belichick said. "You have to get big contributions from other guys -- some at the linebacker position, some at other positions as well -- see how it all comes together. Keep our fingers crossed for him. See exactly what his situation is, but we have to be ready to move on without him.
"So we will have to put multiple groups, multiple players to do some things that he did. I don't think there's one player that's going to run this team and do all that Jerod did. We were lucky to have him, let alone a guy who can do all that too. It will come from a combination of guys somehow."
The Patriots are already thin at linebacker, with starter Dont'a Hightower not playing with a left knee injury. That has thrust undrafted rookie Deontae Skinner and special teamer Chris White into the team's base defense.
This would mark the second straight season that Mayo's season was affected by a serious injury, as he was lost to a torn pectoral muscle Oct. 13, 2013 against the New Orleans Saints.
"It's always tough when you lose a guy like that," Wilfork said. "Don't know exactly what it is, I just talked with him for a little bit at halftime and got back to making adjustments. Haven't really spoken to him. But anybody of that caliber means so much to this team on and off the field, their character and all. That's what it's all about -- who he is as a person first and foremost.
"And being a great leader and contributor to the team, you lose some value there. I'm pretty sure I'll talk to him on the way home and see how he is feeling and stuff like that. But we are going to have to rally around one another."
Quarterback Tom Brady choked up a little when asked about Mayo's injury as he took a long pause before saying, "It's unfortunate."
"Guys like that -- Jerod, we lost Vince last year, we lost a lot of really key, important players -- you just have to keep fighting on and there's a lot of football to play. Those guys have played great football for us and they give everything they can to our team, so it's tough when you lose them."
Information from ESPNBoston.com contributor Lee Schechter was used in this report.