Locker was hurt during the second quarter of the Titans' 29-27 loss to Jacksonville Sunday after taking a hard hit. He limped to the sideline and was replaced by Ryan Fitzpatrick.
The third-year quarterback was found Monday to have sustained a Lisfranc injury, in which bones in the midfoot are broken or ligaments that support the midfoot are torn.
Locker, who also missed two games last month with a hip injury, had thrown for 1,256 yards and eight touchdowns this season, completing 60.7 percent of his passes.
Fitzpatrick will likely get the starting nod for Tennessee in the rest of the season, with Rusty Smith serving as his backup.