Murray sprained the lateral collateral ligament (LCL) in his right knee during last Sunday's loss to the Los Angeles Rams.
Murray didn't practice all week and had a noticeable limp on Friday when walking toward the locker room.
Murray rushed for a career-low 659 yards this season and averaged just 3.6 yards per carry.
Derrick Henry, who has rushed for a team-best 693 yards, will make his second start of the campaign.
"I don't know how many carries I'm going to get, but I'm going to make the best of my opportunities," Henry told reporters.
Quarterback Marcus Mariota feels Henry will perform just fine.
"He's a high-volume guy and I think he continues to get better as he gets reps," Mariota told reporters. "When you have a back like that, I'm sure he's excited and he's chomping at the bit to get out there."
Also, cornerback Logan Ryan (ankle) was listed as questionable for Sunday's game, one the Titans must win as they battle for an AFC wild-card spot.