Townsend was injured in Spurs' 1-0 win at Stoke City on Saturday and will have surgery on his left ankle on Thursday.
"Following further examination and consultation, Andros Townsend is to undergo surgery on his left ankle after damaging ligaments during our fixture against Stoke City last Saturday," a club statement read.
"The injury is likely to sideline the young winger for up to 10 weeks."
Townsend, who left the Britannia Stadium wearing a protective boot and underwent an MRI scan on Monday, burst onto the international stage in October, when he scored in a 4-1 win against Montenegro.
He also featured against Poland four days later as England secured their qualification for Brazil with a 2-0 win.
But his form tailed off back at Tottenham and he last started a Premier League match in the 1-0 defeat to Arsenal on 16 March.
A lack of playing time might have put his Brazil place in peril but Wednesday's diagnosis has sealed his fate.
England manager Roy Hodgson expressed his symapthy for Townsend's predicament, describing it as 'a cruel blow' for the player.
"I am very disappointed." Hodgson told the FA website. "I am disappointed for him in particular, he had a fantastic debut bursting onto the scene and he did really well.
"I have been a bit disappointed for him that he has not had as much playing time over recent months than I was hoping he would get, but to see him ruled out like this with a serious ankle injury, that is a cruel blow.
"My thoughts are very much with him and the only thing I can say is the classic; that he is young, there will be lots of other opportunities. But I am sure that won't make him feel better at the moment because his chance to get into the squad has been taken away from him."
Hodgson will name his provisional England World Cup squad on 12 May.