South Sydney's Adam Reynolds and Newcastle's Mitchell Pearce have both been ruled out of Origin I after the pair suffered injuries in round 11.
The injury curse is added to the absence of Luke Keary, who was ruled out with concussion on Friday night.
Reynolds could miss more than just the Origin opener, with what could be a fractured fibula.
The halfback will have scans on Sunday, with Wayne Bennett addressing the incident post-game.
"It's a lower leg injury, they're not sure what it is at the moment, it's somewhere around the calf area, there could be a fracture,'' Bennett told the media post-match.
"Who was to know if he was going to be picked or not [for NSW]. I'm feeling for South Sydney. We need him to play if we can, if he can't we'll get it done until he's back.
"He was playing great tonight and he's been very good every week. He's had injuries before in football. He's fine.''
Pearce will be joining Reynolds on the sidelines for Game One, with a groin strain ending his chances of selection.
Pearce was originally not in Origin contention, but has been one of the form players of the past month.
Despite now being unavailable for the series opener, Newcastle expect him to be fit for their next game, which comes against South Sydney on Friday week, with the Knights enjoying a bye next weekend.