He skipped practice Friday and was declared out after he missed practice again Saturday.
The former Heisman Trophy winner from Southern California has been sidelined since an MRI Dec. 6 indicated he suffered a partially torn left knee ligament Nov. 25 at Carolina.
This season, his second in the NFL, Bush scored four touchdowns on 157 carries for 581 yards and scored twice after catching 73 passes for 417 yards. He lost three fumbles.
The Saints maintain very slim playoff hopes but the team did not say if Bush will play in the post-season.