Mayo was carted off the field during the second quarter of the Patriots' 37-22 win over the Buffalo Bills on Sunday.
Schefter reports that multiple sources have said the injury to Mayo's lower right leg "is bad."
Mayo, who was a team captain and led New England in tackles, was seen on crutches with a compression band on his knee after the game.
In six games this season, Mayo had 37 tackles with one sack and one fumble recovered.
In his previous six seasons in New England, he amassed 462 tackles, 10 sacks, seven fumble recoveries and three interceptions.
- Christopher Woody