Jack Butland is facing between six and 10 more weeks out of the Stoke City side as he recovers from ankle surgery.
Butland fractured his ankle while representing England in a friendly against Germany in March and has not played in a competitive match since, despite featuring during pre-season.
The goalkeeper opted to have a "minor operation" this week in order to resolve his ankle issue, and manager Mark Hughes said the procedure was a success.
However, he does not anticipate Butland returning before late October, while back-up goalkeeper Jakob Haugaard is also struggling with an ankle issue.
"All reports are that the operation went really well," said Hughes in his media conference ahead of Saturday's match at home to Tottenham.
"It was a little bit of scar tissue that was restricting movement of his tendon. The likelihood is that it will be between six and 10 weeks until we see him.
"Jakob has had a problem with his ankle which is hindering him from kicking the ball as confidently as he would like. We will look at that and if he isn't okay then we have Lee [Grant] here who is more than capable of stepping up."
Xherdan Shaqiri did not feature for Switzerland during the international break due to a calf injury, and Hughes will also be without him at the bet365 Stadium.
"Shaqiri is out - he still has a slight restriction in his calf. He had different treatment this week to try and loosen it, and he has responded well, but he won't be ready," the Welshman added.
"The likes of Geoff Cameron and Ramadan [Sobhi] didn't come back [from international duty] until yesterday so we will check on them today.
"Mame Diouf is another who returned with a slight issue, so the likelihood is that he won't be available for this game."
Saturday's match could bring a debut for Wilfried Bony, who joined on loan from Manchester City last week, and Hughes is excited to see him in action.
"We have been really impressed by him. Even in training you can see the quality he has, and his ability to move into good areas," he said.
"He is scoring four, five or six goals every session we have, and that is a sure sign that he is motivated to do well here.
"He has been in and out of the Manchester City team and I think that affected him detrimentally, because prior to that he was outstanding at Swansea City when he was playing regularly.
"We anticipate him replicating that here. At times we have been guilty of missing the final end product but I sense that Wilfried will address that."