South Sydney on Thursday removed Mitchell from their team list to face Cronulla on Saturday and expect he will be sidelined for the next one to two weeks.
Mitchell has been in resplendent form since making a full-time move to the centres this season and is considered a walk-up starter for NSW in the May 27 series opener.
Should he miss two weeks, Mitchell will not play again before Origin teams are announced after round 11, but would be fit for Origin I.
If he needs longer than that to recover, Mitchell would become yet another prospective member of the Blues' backline to be forced to the sidelines.
Outside backs Tom Trbojevic, Mark Nawaqanitawase and Jacob Kiraz are set to miss the series opener through injury, while Kotoni Staggs is sidelined until then through suspension.
Mitchell's absence is a blow for the Rabbitohs, who endured a season of injury carnage in 2025 but had a cleaner bill of health to begin the new year.
In recent weeks, though, key players Mitchell, Brandon Smith, David Fifita, Jack Wighton and Jye Gray have all been sidelined through injury.
Originally benched to accommodate Ash Ward's return, Jamie Humphreys has also been ruled out of the clash with Cronulla.
The burly playmaker is expected to miss up to two weeks with a leg issue.
Latrell Siegwalt will make his NRL debut in Mitchell's place for the round-10 clash against the Sharks at Accor Stadium.
Mitchell's injury comes only days after breaking his notorious self-imposed media ban to front the press at Souths training.
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