Mathews did not practice all week and was listed as doubtful on the injury report. With the rookie first-round pick out, the Chargers are likely to have Darren Sproles and Mike Tolbert share the running load. Mathews was hurt early in San Diego's win over Jacksonville last week. Tolbert rushed for a career-best 82 yards and two touchdowns in Mathews' absence.
Also inactive for San Diego was starting linebacker Stephen Cooper, who was listed as questionable with a knee injury. Backup linebacker Larry English was also out with a foot injury.
The Associated Press contributed to this report.