Fletcher, who has scored 11 Premier League goals for Sunderland following a summer move from Wolves, damaged his ankle ligaments in Scotland's World Cup qualifying defeat to Wales on Friday night.
The £12 million striker will now be unavailable for Martin O'Neill as Sunderland seek to end a run of seven winless matches that has left the club only four points above the relegation zone.
In another damaging development, skipper Cattermole will also miss the remainder of the 2012-13 campaign.
The tenacious midfielder has played just 10 league games this season due to persistent knee injuries and has undergone surgery.
A club statement read: "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 (Wednesday) 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."
Sunderland next three games see the Black Cats host Manchester United before travelling to Chelsea and then rivals Newcastle United.
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- Lee Cattermole