NFL Media Insider Ian Rapoport reported, via sources informed of the situation, Mayo is believed to have suffered a "significant" knee injury and will have more tests Monday.
"Keep our fingers crossed for him and see exactly what the situation is. (We) have to be ready to move on without him," Belichick said per ESPN's Mike Reiss.
Defensive coordinator Matt Patricia said Mayo's loss will be a huge hit to communication, as Mayo is the quarterback of the defense.
Belichick added that no one player will replace Mayo, who has led the Patriots in tackles in five of the last six seasons.