According to reports, James will require surgery after breaking the fifth metatarsal during practice on Thursday.
Losing the 23-year-old, who started all 16 games as a rookie last season, making the Pro Bowl and earning first-team All-Pro honours - is a huge blow for the Chargers.
They are likely to be without James for the majority of the regular season, though he could return if the team make the playoffs.
The former Florida State standout was the 17th overall pick in the 2018 draft and recorded 105 tackles, three interceptions, 13 passes defended and 3.5 sacks in his debut season.
The Chargers are also without running back Melvin Gordon, who is holding out of training camp due to a contract dispute.
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