Regular skipper Cameron Murray and veteran Damien Cook are missing the game through State of Origin duty, while one-time fill-in captain Mark Nicholls has been sidelined with concussion, paving the way for Mitchell to lead the side for the first time.

After his first game back from injury last week, Mitchell ruled himself out of Origin contention to focus on club duties, in what Demetriou said was only the latest example of the fullback's growth as a leader.

"Over the last couple of years, it's been a steady journey," Demetriou said.

"It's a pretty big sacrifice to leave the (Origin) team and that's part of his journey as a leader. It's a good opportunity for him to step up this week."

Demetriou said he expected Mitchell would inspire the inexperienced players coming into the side as injury and Origin replacements.

"He's done everything in the game," Demetriou said.

"If I was a young player, I'd definitely be leaning towards him."

Mitchell said he considered captaining the Rabbitohs one of the "greatest achievements" of his career.

"It's up there with a grand final for me," he told SEN.

"It's such an honour and a privilege. I've never captained anything in any sport in my life.

"When coach rang me, I was jumping around and cooeing. It's just so important to me."

Heading into the clash with Souths, Newcastle coach Adam O'Brien said he could see parallels between his side's season and their 2021 campaign, which culminated in a finals appearance.

The injury-ravaged Knights have underachieved this year but ahead of round 17 in 2021, were only two competition points ahead of their current ladder position.

Newcastle are preparing to welcome a key member of their spine back from injury against the Rabbitohs, just as they did at a similar point last season.

"There are a lot of similarities with last year," O'Brien said.

"We're very similar on ladder position and we're getting personnel back at the same time that we got (former halfback) Mitch Pearce back.

"But we can't just hope that (finals) are the case again, we need to make it happen."

First-choice hooker Jayden Brailey has recovered from an Achilles tendon injury suffered in pre-season and will start from the bench, while centre Bradman Best has shaken off an elbow complaint and returns to the 17.

"I'll ease (Brailey) in. I anticipate (he will play) 30 odd minutes, we'll see how the game pans out," O'Brien said.

"He's done a lot of solid training, especially over the last five to six weeks."

Australian Associated Press