The running back will miss the rest of the season after MRI results revealed he tore the ACL in his right knee.
Chargers coach Mike McCoy confirmed the ACL injury on Monday afternoon.
"I promise you one thing," McCoy said. "Danny will come back stronger than ever. ... He's a great example of what it means to be a pro."
Woodhead's injury leaves San Diego thin at running back, with just three healthy tailbacks -- Melvin Gordon, Kenneth Farrow and Andre Williams -- currently on the roster.
The Chargers already lost Branden Oliver for the season during exhibition play, because of a torn Achilles tendon. Oliver had a similar skill set to Woodhead as a change-of-pace, third-down back.
The Chargers claimed Williams, a bruising runner, off waivers after the New York Giants released him during final roster cuts earlier this month, but they likely will be in the market for another running back this week.
McCoy also said on Monday that starting safety Jahleel Addae was having surgery to repair a broken clavicle and will be out for an extended period of time. Addae suffered the injury Sunday against the Jacksonville Jaguars late in the game while making a tackle on Denard Robinson.
Dexter McCoil or Adrian Phillips are possibilities to fill in at safety for the Chargers while Addae is on the mend.
Woodhead, 31, was injured Sunday with about two minutes left in the opening quarter, when he caught a pass in the flat and was tackled by Jaguars linebacker Telvin Smith. Woodhead was evaluated by trainers and had to be helped off the field without putting pressure on his right leg.
He received a scare during offseason work when a lineman rolled up on his left ankle in the Chargers' last practice of their mandatory minicamp. He escaped with just a sprain and reported to training camp healthy.
Woodhead broke his right ankle in a Week 3 game against the Buffalo Bills two years ago, ending his 2014 season.
Last season, he finished with the most receiving yards in the NFL for a running back (755).