Everton's Belgium international Marouane Fellaini is out for the season with an ankle injury while fellow midfielder Tim Cahill will be missing for up to three weeks with a foot problem, the club said.
Neither player featured in Tuesday's surprise 1-0 defeat by Reading in the FA Cup fifth round at Goodison Park with the 23-year-old Fellaini needing surgery on the injury he picked up in the 2-0 home win over Sunderland in the league on Saturday.
"Marouane Fellaini is going to be out for the season now, he'll have an operation on Monday," Everton manager David Moyes was quoted as saying on the club's website (www.evertonfc.com).
"Most people will tell you he's been a key player for us this season," he added after Tuesday's loss to the Championship (second division) side.
"Tim Cahill will miss two or three weeks with a foot injury just now, but that isn't a reason for (Tuesday's) result."
Everton, who had knocked out FA Cup holders Chelsea on penalties in the previous round, visit Newcastle United in a mid-table Premier League clash on Saturday.