Pruitt was blocking on a rushing attempt by D'Onta Foreman and got his ankle rolled up on in the pile.
The 29-year-old is expected to have surgery on Monday, a source told ESPN's Jeremy Fowler.
Pruitt pounded the ground with his fist as he laid on the ground. The Titans' training staff immediately motioned for the cart and Pruitt was loaded onto it before being taken into the locker room.
Pruitt has 14 receptions for 145 yards and three touchdowns this season.
The Titans won Sunday's game 34-3.