Elliot Daly has also suffered a knee concern, but England are confident the Saracens star will be fit to start the World Cup.
Luckless wing Watson would have started in England’s first-choice XV, leaving England scrambling to rejig their 33-man squad for the fast-approaching tournament in France.
Gloucester’s Jonny May has been called into the England ranks and will start Saturday’s final World Cup warm-up clash, against Fiji at Twickenham.
England will now face Argentina in their World Cup opener in Marseille on Saturday, September 9 in the midst of an increasing injury and availability crisis.
Steve Borthwick’s side had already lost scrum-half Jack van Poortvliet for the whole tournament to an ankle injury, with Alex Mitchell drafted in.
England must also start the tournament without captain Owen Farrell and talismanic No 8 Billy Vunipola. Farrell will miss both the Argentina and Japan pool matches through suspension, with Vunipola absent solely for the Pumas clash.
England will now be without almost a third of their starting XV for that crucial World Cup opener against Michael Cheika’s menacing Argentina side.
“Anthony Watson suffered an injury to his calf against Ireland that was then investigated,” said England boss Borthwick.
“Anthony is not going to be able to play for a number of weeks, so unfortunately he will not be part of the 33 that will travel to France next week. We wish Anthony all the best in his recovery and hope to see him back fit and firing quickly.
“In the game against Ireland, Elliot Daly suffered an injury to his knee that we expect to leave him unavailable just for this weekend. We expect him to be fully fit at the start of the World Cup.”
England have lost two of their three World Cup warm-up matches, against Wales in Cardiff and last weekend’s five-try, 29-10 defeat by Ireland in Dublin.
Head coach Borthwick’s side have also now not scored a backline try in five hours and 53 minutes. Wings Daly and Watson had been in prime form forcing their way back into not just the England set-up but the starting XV.
Daly had been surplus to requirements under Eddie Jones but Borthwick made the Saracens star one of his most pivotal selections. England will be mightily relieved the former Wasps star can still push to feature at the World Cup.
Watson had shaken off serious Achilles and knee problems that ravaged his last 18 months to work his way back into England’s strongest line-up.
So now England have been forced into another rethink. May went through England’s full preparations ahead of the 33-man World Cup squad selection, and is now in pole position to replace Watson at the World Cup.
“Jonny has trained exceptionally well,” said Borthwick. “The World Cup 33 doesn’t have to be finalised until next week, so after this game next Saturday I will then be confirming exactly who will be going in that 33 next week.”
England have another clutch of players battling to be fully fit in time for the World Cup.
“Henry Arundell suffered a freak back spasm in Ireland that has ruled him out of selection for Saturday,” said Borthwick. “Tom Curry is still working back from an ankle injury. He wasn’t ready to go for the game this Saturday, but he’s very close to being back and fully fit and available.
“George Martin suffered a knee injury in the Wales game at Twickenham, he’s still unavailable for selection this weekend but his return is imminent.”