Woodhead is scheduled for an MRI on Monday, ESPN's Adam Schefter reports.
Woodhead suffered the injury with about two minutes left in the opening quarter when he caught a pass out in the flat and was tackled by linebacker Telvin Smith.
Woodhead was evaluated by trainers and had to be helped off the field without putting pressure on his right leg.
Woodhead, 31, received a scare during offseason work when a lineman rolled up on his left ankle in San Diego's last practice of the team's mandatory minicamp. He escaped with just a sprain and reported to training camp fully healthy.
Woodhead broke his right ankle in a Week 3 contest against the Buffalo Bills two years ago, ending his 2014 campaign.
Last season, he finished with the most receiving yards in the NFL for a running back (755).