Ntamack suffered a ruptured cruciate ligament in his left knee during Saturday's 30-27 warm-up victory for the tournament hosts against Scotland, French sports daily L'Equipe reported.
Ntamack was helped off the field after 55 minutes after opposite number Finn Russell charged into him.
France coach Fabien Galthie, who will announce his World Cup squad on August 21, had seemed unworried after the match, saying the Toulouse player had suffered "a small hyperextension of the knee."
"We preferred to replace him. He was seen by the doctor, the physiotherapists, and we will decide on Sunday if there needs to be additional examinations," he said.
Ntamack seemed to confirm the horrible news on social media, tweeting "I'll be back."
"It will take a little time to digest," Ntamack's father Emile, a former France international who played in the 1995 and 1999 World Cups, told AFP.
"We are still a little in shock, even if he felt it coming since his injury.
"We were hoping for a pleasant surprise this morning (Monday) but we weren't under too many illusions. It didn't feel right. He had already taken blows to the knee and he felt it wasn't as usual."
Bordeaux fly-half Matthieu Jalibert is likely to step into Ntamack's position during the World Cup.
Jalibert started for France during last week's defeat to Scotland when Galthie opted for a rotated line-up.
La Rochelle playmaker Antoine Hastoy is the other flyhalf option in the training squad, who made his debut during 2021's series decider against the Wallabies in Brisbane.
France open their campaign against New Zealand on September 8 in Paris.