Mathews suffered what is believed to be a Grade 2 MCL sprain (partial tear), which typically will keep a football player out from two to four weeks, but a skill position player whose game is built on speed or stopping and starting could miss closer to four weeks or more.
If he only misses four weeks, Mathews would return for the Oct. 19 game against the visiting Chiefs.
Donald Brown likely would fill the void as San Diego's every-down back if Mathews was unavailable for a long time.
Mathews was injured with 12:22 left in the game against Seattle while trying to recover a fumble after a muffed handoff exchange from Philip Rivers. Eddie Royal recovered the ball and appeared to hit Mathews in his knee during the play.
Mathews, who rushed for 31 yards on 11 carries against the Seahawks, was attended to by trainers during the game, was taken off the field in a cart and had an MRI.
Mathews played a full 16-game season for the first time in his NFL career in 2013, finishing with a career-best 1,255 yards. However, a lingering ankle injury limited his effectiveness in the playoffs, and he sat out most of San Diego's AFC divisional playoff loss at Denver.