Cleary junior has been ruled out of Thursday night's clash against the Sydney Roosters with a right-hamstring strain.
His spot at No.7 will be filled by new recruit Brad Schneider.
There is every chance Cleary could also miss the following week's visit to Manly, particularly if Penrith play it safe ahead of their round-six bye.
The 26-year-old's hamstring injury is his second in recent times; last year he suffered a tear to his left leg.
"Nat seems to have a sabbatical every year, this one's a bit earlier," Ivan Cleary said on Tuesday.
"It's not too bad, that's the pleasing thing. He felt the same thing last year before he actually did it properly.
"The fact that he had that experience means we cut this one off a bit sooner. Hopefully it'll only be a couple of weeks."
The Penrith coach speculated the current setback was potentially related to a pre-existing injury in Nathan's foot - rather than a wider issue affecting his hamstrings.
He hoped the No.7 could return fitter and stronger next month.
"He's had a (plantar) fasciitis injury in his foot since pre-season. Sometimes that plays a part," Ivan Cleary said.
"He's been struggling with that for a bit. This might be a silver lining, where he can fix that up as well in the meantime."
Jarome Luai will likely take the lead on Penrith's attack, in a sign of things to come for him ahead of next year's switch to be Wests Tigers' chief playmaker.
"It's an opportunity for everyone to sharpen up and step up. Romy's definitely in that category," Ivan Cleary said.
With Scott Sorensen sidelined with a knee injury for the next month, and James Fisher-Harris (shoulder) also still out, Penrith will hand an emotional debut to Mavrik Geyer.
The son of Panthers legend Mark Geyer, Mavrik has further links to the club through uncles Greg Alexander and Matt Geyer.
Long touted as a potential first-grader, the 23-year-old will feature off the bench for Penrith.
"He's a bit of a late bloomer who didn't really get serious about his footy until probably three years ago," Ivan Cleary said.
"He's been playing well at Cup level and training really well.
"This pre-season has been outstanding and he's ready now to take the next step.
"He's a pretty big lad. I didn't get the joy of playing with MG (Mark Geyer), but I played against him and tried to avoid him as much as I could.
"They're a little bit different, and the game is a bit different these days. I haven't seen (the same mean streak in Mavrik)."
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