The injury will end Mathews' season, the San Diego Union-Tribune reported.
Mathews broke his right collarbone on his first carry of the team's preseason opener. That injury forced him to miss San Diego's first two regular-season games.
Mathews had just four carries for 22 yards and three catches for 8 yards before leaving with the injury Sunday.
"I just hate it for him," fullback Le'Ron McClain told the Union-Tribune. "Just him bouncing back the way he did after the first one. Going into the game, he felt good today. I could see a different look in his eyes today. We were giving the ball a few times, seeing what he could do. He made a few plays, a few great runs. It sucks to come down with an injury like that."
Information from The Associated Press was used in this report.