Watson sustained the problem in Saturday's defeat against Ireland in a World Cup warm-up fixture.
The 29-year-old has been replaced in Steve Borthwick's World Cup squad by Jonny May, who will start Saturday's clash against Fiji.
It is the latest fitness issue for British and Irish Lions wing Watson, who has battled back from long-term knee and Achilles injuries.
The injury is another huge setback for England boss Borthwick in the same week that captain Owen Farrell and number eight Billy Vunipola were handed bans that rule them out of the World Cup opener against Argentina on September 9.
"In the game against Ireland, Anthony Watson suffered an injury to his calf which means he can't play for a number of weeks," Borthwick said.
"As such he will not be part of the 33 that travels to France next week. We're all really disappointed for him."
Watson is the second player to withdraw from Borthwick's original World Cup squad after an ankle sidelined Jack van Poortvliet.
Borthwick also reveal on Thursday that Elliot Daly and Henry Arundell have been ruled out of the Fiji match.
Daly suffered a knee issue against Ireland, but England are confident he will recover in time for the World Cup, while Arundell has been struck down by a "freak back spasm".
Courtney Lawes will captain England in the absence of Farrell as the lock wins his 100th cap against Fiji this weekend.
With Farrell serving a four-match suspension, Lawes will have the honour of skippering the team at Twickenham when he becomes the fifth England player to amass a century of Test appearances.
Lawes made his debut as a 20-year-old against Australia in 2009 and has played some of his best rugby in the twilight years of his Test career.
"We couldn't be prouder of Courtney on achieving his incredible milestone after 14 years of excellent performances for his country," Borthwick said.
"It has been a privilege to watch his journey and witness him develop into a truly outstanding rugby player.
"Not only is Courtney an exceptional talent and an excellent professional, he is also a brilliant role model for young players every time he steps onto the field."
