South Sydney will sit State of Origin stars Damien Cook, Cameron Murray, Dane Gagai and Jai Arrow against Newcastle to avoid them playing three games in eight days.
Rabbitohs coach Wayne Bennett confirmed on Friday that both Latrell Mitchell and Jaydn Su'A would back up three days after Origin I, but the rest of his players would be rested.
Souths have a rough run through the Origin period, with an away trip to Brisbane kicking off round 15.
Cameron Murray has also battled injuries in the lead-up to the representative period, while Gagai and Arrow were left off Bennett's original team list.
In better news for the Rabbitohs, it is believed Gagai has not suffered a serious hand injury after hurting it in Queensland's heavy loss in Townsville.
"He still hasn't got a scan on it. But there is enough movement there for us to think it's not broken," Bennett said.
"But you know if you keep pushing them or pushing them they will either break down or their form goes off a bit as well.
"So you give them the opportunity to have six or seven days off and they will play on Thursday night in Brisbane.
"But three games in eight days isn't easy."
The decision to rest Cook will make for the first time the hooker hasn't run out for South Sydney since way back in round 12, 2018.
At that point they still had Billy Brittain in their squad as cover, but the solution is now less obvious.
One option could be to shift a half or Benji Marshall into the role, otherwise uncapped rookies Blake Taaffe or Peter Mamouzelos could come into contention.
Taaffe is seen as the potential heir apparent to Adam Reynolds next season, but the 22-year-old is yet to play first grade after suffering an ankle injury in the Charity Shield.
Mamouzelos is seen as an out-and-out hooker, with the 20-year-old having previously represented Greece.
Meanwhile Bennett said Mitchell had been quiet on his return to Rabbitohs training on Friday, but had no concerns over a letdown come Saturday.
The veteran coach also claimed the 23-year-old was nowhere near reaching his ceiling, after his best night in represenative football for NSW on Wednesday.
"I'm sure we haven't (seen the best in him)," Bennett said.
"It's just a process, each year he will get better.
"I enjoyed watching him play, I always did even when he wasn't here.
"That's why I was so keen on the opportunity to bring him here. He's a wonderful player and I love the way he plays the game."