Mitchell is expected to play no part in the July 17 decider at Suncorp Stadium because of a foot injury, with Maguire due to name his team for Origin III on Sunday.
Maguire would have entered this weekend hoping to be able to go into the decider unchanged, with NSW humming following their 38-18 win in Melbourne.
Instead, he has been handed one of the worst possible setbacks with the intimidating Mitchell thought to have suffered a potentially season-ruining foot injury.
Souths sent their star fullback for scans on Saturday with Mitchell to meet with a specialist in coming days to assess whether he requires an operation.
Mitchell's absence is a blow for the Bunnies, who remain in the frame for a late charge towards the finals, as well as Blues coach Maguire.
NSW coach Michael Maguire has some big selection calls to make for the State of Origin decider. (Con Chronis/AAP PHOTOS)
The saving grace for Maguire is he does have options to fill the void at left centre.
Bradman Best will likely be the leading contender, having scored a double for NSW on debut last year, before injury ruled him out of Origin I last month.
Best must first get through the Knights' clash with Canberra unscathed on Sunday afternoon, with Maguire to name his squad almost immediately after the game.
Joseph-Aukuso Suaalii is also available again after his ban for hitting Reece Walsh high in Origin I, with his four-game suspension now served.
Tom Trbojevic and Matt Burton are the other options, with the former indicating he felt he would be ready for Origin after his return for Manly on Saturday night.
Burton, meanwhile, is the man with the momentum.
The two-time NSW centre said he would be ready if recalled on the back of his second game-winning performance for Canterbury in as many weeks.
Burton was unaware Mitchell's Origin hopes had been thrown into doubt when he slotted a field goal to sink the Warriors 13-12 in extra time on Saturday.
"I don't really know (about Mitchell's injury)," he said.
"I'd be more than open to putting my hand up for NSW if they needed me. I'm ready."
The 24-year-old was 18th man for the series opener - a role he has filled three times across the past two series.
He is keen to get back in camp if chosen at left centre, the position he played in Penrith's 2021 premiership triumph.
"You can see in game two what they showed, there's something special building there," Burton said.
"It was unreal to be around the boys in game one."
NSW right centre and Bulldogs captain Stephen Crichton believed Burton's recent clutch performances for Canterbury proved his Origin mettle.
"He just didn't shy away from it, trusted his process, and he's done the same before playing centre as well," Crichton said.
"He knows how to defend at centre and how to read shapes when they come. I'd definitely have confidence in him if he is selected for that left centre."
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