Penrith Panthers coach Ivan Cleary is set to take an unprecedented course of action by resting up to 13 players for the Round 25 clash against the North Queensland Cowboys.

It's a game which ultimately means nothing for the men from the foot of the mountains, who lifted the minor premiership after last weekend's win over the New Zealand Warriors.

They sit six points clear of the competition with one round to play, and while the currently second-placed Cronulla Sharks would probably prefer Penrith to beat the Cowboys so they can lock up a home qualifying final without playing, that isn't the course of action the Panthers are interested in taking.

The Western Weekender's Peter Lang is suggesting the Panthers will rest 13 players for the final round clash, something which will leave an almost unrecognisable squad for the trip north to Townsville on Saturday evening.

Coach Cleary has previously promised that he would rest players ahead of the last round following what has been a busy season for the Panthers, where seven players were involved in State of Origin.

Of their eight Origin players, Jarome Luai has only just come back from injury and Liam Martin missed the win over the New Zealand Warriors, while Nathan Cleary is currently out suspended.

Still, the talk has been that Luai will be rested again, although the star five-eighth told reporters that he wants to play after Friday's win.

It's unclear at this stage whether Martin will be given another week off or brought straight back into the team.

All of Stephen Crichton, Brian To'o, Apisai Koroisau and Isaah Yeo however are likely to be rested for the trip north.

Joining the quartet on the sidelines are likely to be a host of players who have either played 20 or more games, or haven't had a rest due to injury or suspension in some time.

Dylan Edwards, Izack Tago, Moses Leota, James Fisher-Harris, Viliame Kikau and Spencer Leniu, who has appeared to be battling an arm injury in recent weeks are almost certain to be rested, while Taylan May had a game off due to injury a few weeks a go, but could be given another rest by Cleary.

Penrith's team for the trip to Townsville will be named at 4pm (AEST) on Tuesday.