The Blues No.7 limped out of Penrith's 26-18 win over St George Illawarra on Sunday, with scans on Monday revealing a grade-two tear to his left hamstring.
The injury is set to sideline the playmaker for "up to six weeks", according to the Panthers.
That diagnosis certainly rules him out of the must-win Game II in Brisbane on June 21 and leaves him at long odds to feature in Game III in Sydney on July 12.
"It's disappointing for him because he loves playing for Penrith, he's a key factor for us performing well," Panthers lock Isaah Yeo said after the Dragons' clash.
"It's the same as Origin, it's disappointing because he's worked so hard on his game.
"That's footy sometimes, you have those unlucky moments.
"But what I do know is that he'll attack his rehab better than anyone."
Cleary cut a forlorn figure on the sidelines at BlueBet Stadium on Sunday and NSW coach Brad Fittler is likely to be experiencing similar feelings as the Blues bid to save the series in Brisbane.
Cronulla's Nicho Hynes, Parramatta No.7 Mitchell Moses and Brisbane halfback Adam Reynolds are all possible candidates to replace the Penrith man.
All three have experience within the Blues set-up, with Hynes debuting off the bench in last week's series-opening defeat in Adelaide.
Cleary's Penrith and NSW teammate Brian To'o said Hynes could fill the void in Brisbane.
"Clez's job is to direct us and tell us where to go," To'o said.
"Whether he plays or not, I'm sure whoever steps up will get the job done.
"Nicho is definitely someone who takes a lot of pride in playing footy and he can live up to the jersey and do his job for the team."
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