Defenders Chris Smalling and Phil Jones suffered "long-term injuries" while on duty with England, Manchester United boss Jose Mourinho revealed at his Friday's press conference.
Jones, 25, picked up a toe injury in an innocuous training ground tackle, with reports claiming it involved Smalling.
And fellow centre-back Smalling, 27, was pictured with a leg brace following an injury also suffered in training.
United captain Wayne Rooney returns for Saturday's Premier League game against West Brom after recovering from a knee injury.The 31-year-old has missed United's last four games.
As a result of the injuries to Smalling and Jones, Mourinho has also included 19-year-old defender Axel Tuanzebe in the squad. The teenager has only made one appearance for the club – in the 4-0 FA Cup win over Wigan in January.
Msnchester United will also be without striker Zlatan Ibrahimovic and midfielder Ander Herrera, who are both suspended, and France midfielder Paul Pogba, who has a hamstring problem.
Asked l how long he expects to be without Jones and Smalling, the United boss said: "I don't know, I don't know.
"I know that Zlatan and Herrera have the last match ban, so it's easy to say they will be available after the match.
"I think clearly the two English boys they are long-term injuries and Pogba I have no idea. I don't know."
Meanwhile, Mourinho said he regretted the way he treated Bastian Schweinsteiger and apologised to the midfielder before his switch to the Chicago Fire.
The Germany World Cup winner, who joined United in 2015, trained with the reserves following Mourinho's arrival in the summer, but was brought back into the first team in late October.
However, last week the 32-year-old was permitted a move to join the MLS side.
"He's in the category of players that I feel sorry for something that I did to him," Mourinho said.
"The last thing I told him before he left 'I was not right with you once, I have to be right with you now'.
"So when he was asking me to let him leave I had to say 'yes, you can leave' because I did it once, I cannot do it twice.
"I will miss a good guy, a good professional, a good influence in training – a very good influence."