Mathews' performance gave him 1,111 rushing yards on the season, surpassing his previous career high of 1,091 set in 2011.
Philip Rivers went 19-of-29 through the air for 201 yards with a touchdown pass to Kennan Allen and an interception as the Chargers (8-7) notched a fourth win in five games.
San Diego needs a victory over Kansas City next week and losses by Baltimore and Miami to claim an AFC wild-card berth.
The Raiders (4-11) dropped a fifth straight, with Matt McGloin passing for 206 passing yards with an interception.
Darren McFadden scored Oakland's only touchdown.