The Panthers are currently sitting on a 1-4 record on the season.
Rhule, who coached the team to an 11-27 record in two-plus years with the Panthers, is the first NFL head coach to be dismissed this season.
Rhule's firing Monday came less than 24 hours after a 37-15 loss to the San Francisco 49ers and less than three years into a seven-year, $62 million contract he was given in January 2020 to turn around the Panthers the way he did college programs at Temple and Baylor. Rhule is still owed north of $40 million.
He will be replaced on an interim basis by defensive pass game coordinator/secondary coach Steve Wilks. The 53-year-old Wilks spent one year as head coach of the Arizona Cardinals, and six years on the Panthers staff from 2012-17.