Vunipola, who has been replaced in England’s training squad by Harlequins’ Jack Clifford, was helped from the pitch just before half-time in Saracens’ victory over Sale on Saturday.
After undergoing scans on the injury, he was sent straight for an operation which will sideline him for up to four months.
The England No8 had only just made his comeback the previous week from the shoulder injury which caused him to miss the Lions tour.
“For any team to lose a player of the ability of Billy is a blow and he will be missed through the autumn for both Saracens and England,” said Saracens director or rugby Mark McCall.
“It’s desperately disappointing for him, considering how hard he has worked during the off-season to get back to full fitness, but Billy is a resilient character and he’ll have a strong support network around him to get him back on the field in the best possible shape.
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“What’s now important for Billy is his recovery and we look forward to his return later this season.”
It is the same knee – the right one – which Vunipola injured against Argentina last autumn. That injury required a three-month recovery period.
The 24-year-old also damaged ligaments in it against Wales at the 2015 World Cup, ruling him out of the remainder of the tournament.
Chris Robshaw (head) and Marcus Smith (calf), who both went off injured in Harlequins’ home defeat against Leicester, were able to join up with the national squad last night for their three-day camp in Oxford.
Club-mate Clifford, who won the last of his 10 caps against Italy in last season’s Six Nations, was summoned to join them by Eddie Jones after an impressive display in front of the England coach at The Stoop.
Just how much value the training camp – which is supposed to lay the foundations for the Twickenham Tests against Argentina, Australia and Samoa in November – will prove to be is debatable with several other players also unlikely to play much part.
Anthony Watson, who missed Bath’s home defeat to Newcastle, is struggling with a knee injury while Joe Marler was also stood down at the weekend with rib damage.
Captain Dylan Hartley, who sat out Northampton’s game at London Irish yesterday, has a hand problem while Saints team-mate Piers Francis has yet to start a game for his new club because of a jaw issue.
Jones’ first-choice full-back Mike Brown also aggravated an ankle injury against the Tigers and is unlikely to be able to take an active role in the three-day camp.
“He was in quite a bit of misery,” said Quins director of rugby John Kingston. “He managed to stay on to make sure we weren’t short of players.”