Mathews was injured on his first carry of the preseason in the first quarter and did not return to the game. He is expected to have surgery Friday morning and coach Norv Turner said he'll be out four to six weeks.
Mathews was involved in a car crash on Monday, but said he was only banged-up and was able to play Thursday.
Mathews, who replaced LaDainian Tomlinson as San Diego's feature back in 2010, ran for 1,091 yards and six touchdowns last season. He added 50 catches for 455 yards.
The Bakersfield native is a former West High Viking and Fresno State Bulldog.