The night before Laurie Daley was due to announce his team, Mitchell informed the Blues coach he would need to miss game one to recover.
It's a crushing blow for NSW, with the South Sydney star considered a lock to play left centre if fit.
Mitchell will also miss at least next weekend's clash with North Queensland at NRL level but could return after the Rabbitohs' round-13 bye.
"Mitchell advised Daley and his South Sydney Rabbitohs club officials that he was not 100 per cent fit and did not want to let down his state or club," a NSW Rugby League statement read.
Mitchell had a quieter Origin series last year by his lofty standards but has been in superb form since making a full-time shift from fullback to the centres in 2026.
He originally suffered his injury in the Rabbitohs' round-nine loss to Newcastle and was expected to miss a maximum of two weeks.
The 28-year-old returned after just one week, only to leave Friday's loss to the Dolphins in the 73rd minute with his Origin hopes in doubt.
The Blues had been expected to name Mitchell on their team sheet and manage his injury in camp ahead of game one in Sydney on May 27.
They took a similar approach with Payne Haas and Brian To'o last year and the pair overcame their injury issues to finish the series as the Blues' best players.
But Mitchell took the decision out of NSW's hands, leaving Kotoni Staggs, Tolu Koula and Casey McLean as selection options at left centre.
Brisbane premiership winner Staggs has missed the past two weeks through suspension but was in fantastic form before that and has played Origin once before.
Koula and McLean are uncapped but have had strong years for Manly and Penrith, respectively.
Canterbury captain Stephen Crichton has already been told he will retain his right centre spot despite questions over his form and shoulder injury.
Out of sorts since returning early from a serious AC joint injury, Crichton showed glimpses of his best form from his three-time premierships with former club Penrith in Canterbury's loss at Magic Round.
Crichton has appeared tentative in his defence and passing since returning in round seven, but has not missed a Blues games since his debut in 2022.
He will be included on Daley's team sheet on Monday morning.
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