The blockbuster clash headlines a selection of "signature" fixtures released by the NBA, with the announcement also revealing that James will return to Los Angeles on Christmas Day to face his former team, the Lakers.
Four-time NBA champion James, who signed for the Sixers on a two-year, $8m contract in July, will face the Cleveland Cavaliers - with whom he won the NBA title in 2016 - in his first home game in Philadelphia on October 22.
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Opening night, taking place on October 20, also features a clash between the Boston Celtics and the Detroit Pistons at 8pm UK time, before the Oklahoma City Thunder take on the San Antonio Spurs in a rematch of last year's Western Conference finals in the late game.
The Christmas Day slate kicks off with an NBA Finals rematch between the San Antonio and the Knicks, before Giannis Antetokounmpo's Miami Heat travel to Boston to face the Celtics.
The NBA also announced that French sensation Victor Wembanyama and the Spurs would be heading to Paris in January to face the New Orleans Pelicans, before the two teams travel to Manchester in the first-ever NBA game at the Co-op Live Arena.
Full NBA Signature schedule announcement
October 20 (opening night)
Boston Celtics vs Detroit Pistons
Philadelphia 76ers vs New York Knicks
Oklahoma City Thunder vs San Antonio Spurs
Oct 21
Minnesota Timberwolves vs Miami Heat
Golden State Warriors vs Los Angeles Lakers
Oct 22
Cleveland Cavaliers vs Philadelphia 76ers
Denver Nuggets vs Oklahoma City Thunder
Oct 23
New York Knicks vs Boston Celtics
Houston Rockets vs San Antonio Spurs
Christmas Day
San Antonio Spurs vs New York Knicks
Miami Heat vs Boson Celtics
Philadelphia 76ers vs Los Angeles Lakers
Oklahoma City Thunder vs Minnesota Timberwolves
Denver Nuggets vs Golden State Warriors
NBA Paris and Manchester
Jan 14 - New Orleans Pelicans vs San Antonio Spurs - Accor Arena, Paris
Jan 17 - New Orleans Pelicans vs San Antonio Spurs - Co-op Live Arena, Manchester
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