Williamson, the first overall pick in the 2019 NBA Draft, underwent tests on the knee on Friday when soreness persisted.
Williamson, who has been described as the best prospect since superstar LeBron James, has undergone surgery to fix a torn right lateral meniscus.
A six-week recovery timeline would put Williamson back on the court in early December.
Williamson averaged 23.3 points in four preseason games. After just eight minutes, the Pelicans shut Williamson down for the summer, although they said they were just being overly cautious.
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New Orleans opens the season Tuesday at Toronto. Zion could miss over 20 games.
While it remains to be seen how coach Alvin Gentry will change his rotation in Williamson's absence, it appears 6-foot-9, 235-pound forward Nicolo Melli of Italy could be in line for more playing time.
"It's still the start of the season".
The rookie signed a US$75 million sneaker deal with Nike before playing an National Basketball Association game.
"To win a championship and have an impact on the team, that would be my dream rookie season", he said. "We'll hold it down as best as we can without him".