The Los Angeles Lakers star will not play against the 76ers due to a left knee injury, according to coach Frank Vogel.
The coach said that James woke up with some pain in his knee. The team had listed him as questionable before he was ruled out.
James is day-to-day, so his availability for Friday is in question.
James missed 12 of the first 23 games this season because of an ankle injury, a suspension and a false positive result on a COVID-19 test. Without him in the lineup, the Lakers are 4-7, compared to 19-17 with him.
James scored 25 points or more for the 18th game in a row, as L.A. started its six-game road trip with a win in Brooklyn.
The 19-year veteran said recently that he was in one of the best zones in his career.
James is one game away from passing Kobe Bryant on the career games played list. Two years ago this week, James passed Bryant in career points in Philadelphia, just before Bryant and seven others died in a helicopter crash.
The Lakers welcomed Anthony Davis back from a 17-game absence Tuesday and signed forward Stanley Johnson to a contract for the remainder of the season.