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North Queensland will be without six State of Origin stars as they attempt to clinch their first NRL win at Penrith since 2016.

North Queensland have a mountain to climb to secure two points from their trip to three-time reigning NRL premiers Penrith, with six of their State of Origin stars rested from the clash.

Reece Robson, Valentine Holmes, Murray Taulagi, Tom Dearden, Reuben Cotter and Jeremiah Nanai have all been left out of Todd Payten's side for Sunday's clash after featuring in the Maroons' crushing 38-18 loss to NSW on Wednesday.

But they will be encouraged that the Panthers will also be without a bunch of Origin stars.

The Cowboys are the NRL's most Origin-affected team but the rest of the squad are newly refreshed after enjoying their first bye of the season following a thumping 34-16 victory over Canberra in round 15.

"The timing is perfect," Payten said.

"The performance was good. We're going to have to back it up against a really good team this weekend."

The Cowboys have lost five straight at Bluebet Stadium but look to have turned their form around after a patchy 8-7 start to the season.

"It's the toughest road trip in the competition," Payten said.

"We had a fair bit to play for last year and we didn't get it done. But we left that in the rear-view mirror a long time ago.

"We're in a reasonable spot, I would have liked to have had a couple more wins under the belt.

"Fingers crossed we can get through this Origin period with all those boys intact and then keep our key players fit and on the ground and playing each week."

Panthers coach Ivan Cleary watched five of his squad line up in Origin II, with only captain Isaah Yeo from that group named to back up on Sunday.

Dylan Edwards, Brian To'o, Jarome Luai and Liam Martin have all been given another week to refill their tanks.

Even without a clutch of star players, Cleary knows Penrith have the depth to perform.

Despite missing talismanic halfback Nathan Cleary for the last seven weeks, the Panthers have managed to maintain their top-two position on the ladder.

Penrith's imperious form over the last three years - they celebrate 1000 days as NRL champions on Saturday - has allowed them to take a cautious approach with team selections and not be forced into rushing players back too quickly.

The younger Cleary is expected to return in round 20, with his coach not tempted to bring him back ahead of a bye in round 19.

"It helps if you've got a few wins in the bank, for sure," Cleary senior said.

"That's why it's important that you try and get some momentum early in the season.

"Any coach will tell you it's much easier to make these decisions if you're at the right end of the table."