Since becoming the Titans' first-choice quarterback, Tannehill has not missed a game for Tennessee.
However, earlier this week Tannehill was noted as questionable due to an ankle injury sustained against the Indianapolis Colts in Week 7 and it was later confirmed he was also struggling with illness.
On Saturday, Ian Rapoport of the NFL Network confirmed Tannehill has been downgraded to out and will not travel with the team to Texas.
Tannehill has completed 95 of 146 passes and thrown for six touchdowns for a Titans side who are 4-2 and top of the AFC South this season.
Willis will instead start under center for the Titans and he has been rep-heavy in practice with Tannehill unable to train.
His only action in the NFL came during Week 2 when the Titans were hammered 41-7 by the Buffalo Bills, with Willis completing one of four passes.
The 23-year-old was selected in the third round of the 2022 NFL Draft, and 86th overall.