Latrell Mitchell has been ruled out of State of Origin game two in Brisbane next week, dealing a huge blow to NSW's level the series.

A calf strain has kept Mitchell off the park for his club side, South Sydney, since mid-May and saw the 25-year-old miss the Origin opener in Adelaide a fortnight ago.

Despite being under an injury cloud, he was again called into the Blues' camp on Monday.

NSW reportedly allowed a Souths physio into their camp to keep an eye on Mitchell, as well as in-doubt Rabbitoh Cameron Murray.

Mitchell is understood to have withdrawn himself from the contest.

Coach Brad Fittler conceded it was a significant loss for his side.

"He tried but realised he wasn't going to be right," Fittler told the Sydney Morning Herald.

"We lose one of the best players in the game. But you'd have to ask him how hard it was to do it (take himself out) twice."

According to reports, Mitchell has managed only minimal training loads and was absent from Blues media commitments on Wednesday to continue his rehab.

On Thursday he went to Fittler to confirm he is unavailable for game two.

"He had a chat with Freddy and said it hasn't come up as quickly as they thought," Alexander said via SMH.

"After Wednesday's (rehab) session, there was still a fair bit he had to get through on Friday and Sunday, but it hadn't come on as quickly as anyone would have liked.

"Disappointingly, he took himself out of the picture."

Penrith's Stephen Crighton, who was pushed back out to 18th man after a solid performance in game one after Mitchell was named in the side this week, will return into the centres at Suncorp Stadium.

Mitchell has made seven Origin appearances since his debut in 2018.

He similarly pulled himself out of last year's series with injury.