Mathews, who injured his ankle in Sunday's loss to the New England Patriots, hasn't practiced this week.
Mathews' availability is among the keys for San Diego (8-5) as it tries to avoid a season sweep by the visiting Broncos (10-3).
With a win, the Chargers retain at least the AFC's No. 6 seed for the playoffs.
If the Broncos prevail, Denver clinches its fourth straight AFC West title.
But without Mathews, the Chargers' running game is diminished. Minus a ground attack, the pressure falls on quarterback Philip Rivers against Denver's challenging pass rush.
"He's working as hard as he can to get out there and get ready to go on Sunday," Chargers coach Mike McCoy said of Mathews. "He's like every other player. Everyone's working hard. We'll play the healthiest 46 to help us win the game."
Mathews, who is in a contract season, has had an uneven year while rushing for 330 yards and three touchdowns.
He missed seven games after hurting his knee on Sept. 14 against the Seahawks. He's eclipsed 100 yards rushing once in his four games back.
Last season, Mathews was productive down the stretch. He rushed for an NFL-high 534 yards in December as the Chargers won four straight to snap their three-year streak of missing the playoffs.
There's a chance Mathews could go Sunday despite his lack of practice.
"He's played plenty of football in his career and he knows what to do," McCoy said. "And he's been in the system for the two years we've been here together."
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