Seb Larsson has been ruled out for up to six months after undergoing knee surgery - with Sunderland boss David Moyes facing a major midfield headache ahead of Manchester City.
Lee Cattermole (groin) and Jan Kirchhoff (hamstring) have also been ruled out of the game at the Etihad Stadium, while right-back Billy Jones won't feature either due to his hip injury.
It means new signing Paddy McNair, 21, is expected to start the game against City in central midfield, while Donald Love and Josh Robson battle it out for the right-back spot.
Larsson missed three months of last season with a knee injury but returned to end the season and play for Sweden at Euro 2016.
Scans revealed he needed an operation to fix a frayed ligament in his knee though and he will now be out until the New Year.
"Seb Larsson is out for five to six months," said Moyes.
"He had a knee injury during last season, a frayed ligament. He went to the Euros and came back and needs the operation.
"He has had that done and they think it will be five to six months.
"Lee Cattermole had a bit of a fitness test this morning but he hasn't trained for three days.
"He his feeling something in his groin, we're not sure if it is a hernia or something.
"I think he has had a history of that. Jan Kirchhoff is his hamstring that he did in the game in France.
"It wasn't serious, it was a small hamstring tear but he hasn't really recovered enough to be close. He is out on the grass doing some light running.
"Billy Jones has a hip problem, which keeps him out as well.
"Those are the four, the main ones."
It means Moyes is facing a headache in midfield and at right-back ahead of the opening day of the Premier League season.
"The biggest thing is we are really short of midfield players, generally," said Moyes.
"We need to try and get some midfield players in. We did need to anyway but these injuries make it bigger.
"Paddy McNair is probably more of a midfield player than defender, he played for Northern Ireland in midfield.
"Donald Love is more of a full back that can play midfield if needed. Because we are so short at full-back, we have a real shortness in those areas.
"We have added three of four - Papy [Djilobodji] gives us competition at centre-back and is left-footed, which is what I wanted.
"He played for Werder Bremen last year, played every game and all the people I spoke to in Germany said he was fantastic.
"I need to get them introduced. The games are coming very thick.
"In some way, they will nearly all be involved [against Manchester City] because of our numbers and the injuries."