According to NFL Network's Mike Garafolo, James will undergo surgery to repair a stress fracture in his fifth metatarsal.
James suffered the injury Thursday during practice, and he was seen in a walking boot the following day.
Garafolo added that James' timeline for return will be clearer after he undergoes surgery and that three months may be the minimum he misses. He also noted James' returning in mid-November may be the "best-case scenario."
After L.A. selected James out of Florida State with the 17th pick in the 2018 draft, he enjoyed one of the best rookie seasons by a safety in recent memory.
James started all 16 games and finished with 105 tackles, 3.5 sacks, three interceptions and 13 passes defended en route to being named first-team All-Pro and a Pro Bowler.
He also registered 14 tackles and three tackles for loss in two playoff games, and he played a significant role in the Chargers' 12-4 finish and return to the postseason for the first time since 2013.
James can do it all, from covering wide receivers and tight ends to defending the run to rushing the passer. Because of his versatility, the Chargers are ill-equipped to replace him.
The top candidate to start in place of James is Adrian Phillips, who was a first-team All-Pro and Pro Bowler as a special teamer last season.
Phillips, 27, is entering his sixth season, all with the Chargers, and is coming off his best statistical campaign. He played all 16 games and made seven starts, finishing with 94 tackles, nine passes defended and one interception.
Meanwhile, Desmond King II and Rayshawn Jenkins are expected to play free safety across from Phillips because of their ball skills.
James' injury was another big hit to the Chargers during what had already been a difficult preseason. In addition to James' landing on the shelf, the Bolts are without running back Melvin Gordon III, who is holding out for a new contract, as well as offensive tackle Russell Okung (pulmonary embolism) and wide receiver Keenan Allen (ankle).