Fletcher suffered ankle ligament damage on international duty with Scotland last week, and midfielder Cattermole underwent surgery on a persistent knee problem on Wednesday.
A club statement said: "Sunderland have confirmed today that striker Steven Fletcher and captain Lee Cattermole will miss the rest of the current campaign due to injury.
"Cattermole underwent an operation on his knee earlier today and Fletcher sustained ankle ligament damage whilst on international duty with Scotland.
"It is not known at this stage if Fletcher will require an operation, with the injury requiring further assessment in the coming weeks.
"Both players will play no further part in the Black Cats' 2012-13 Barclays Premier League season."
The news could hardly have come at a worse time for Martin O'Neill, whose side finds themselves firmly entrenched in a battle for top-flight survival with eight games of the campaign to play.
They face leaders Manchester United at the Stadium of Light on Saturday desperate to end a run of seven league games without a victory which has yielded just three points and left them only four clear of the drop zone.
Fletcher in particular will be a huge loss after paying off a large proportion of the £12million the club invested in him during the summer with 11 goals.
However, having scored five in his first four games for the Black Cats, he has managed only one in his last seven, with the supply lines having dried up alarmingly.
The 26-year-old former Wolves frontman was injured just two minutes into Scotland's 2-1 home defeat by Wales in Friday night's World Cup qualifier at Hampden Park and was carried from the field on a stretcher.
If he does need surgery, player and manager alike will hope he can return in time for the start of the new campaign.
O'Neill at least has January signing Danny Graham, who has played alongside Fletcher in recent weeks, at his disposal.
Cattermole has been plagued by injuries for much of his time on Wearside and has managed only two senior appearances since the end of November.
He had an injection in his injured knee several weeks ago in a bid to solve the problem once and for all, although O'Neill admitted at the time that an operation was a possibility.
Having visited his specialist again, the decision was taken to perform the surgery and write off the rest of the campaign.