The Rabbitohs confirmed on Saturday that Murray had suffered a hip flexor injury in Thursday night's loss to Penrith, ruling him out for between six and eight weeks.
It means the Souths captain is no chance of playing for NSW in the series opener on June 5, and would be an unlikely chance to be fit for Game II on June 26.
The backrower has been a regular in Origin for the Blues since his 2019 debut, missing only two games through injury since then in 2020.
But he has appeared battered and bruised through Souths' nightmare start to 2024, with the last-placed Rabbitohs struggling for form across the park.
Murray's injury will further strengthen Haumole Olakau'atu's Origin case, with the Manly second-rower a strong chance to debut at Accor Stadium.
Angus Crichton could well join him either starting or off the bench, with the Sydney Roosters second-rower in fine form after starting the year in reserve grade.
Liam Martin and Isaah Yeo are the other backrowers almost certain to appear in coach Michael Maguire's 17 when he reads out his maiden Origin team later this month.
Murray's injury comes as another hit to the Rabbitohs, whose continual setbacks this season resulted in coach Jason Demetriou being axed last Tuesday.
Prop Tevita Tatola, centre Campbell Graham and young winger Tyrone Munro are all sidelined long term through injury.
Rising star Jye Gray suffered an ankle injury against Penrith, while superstar fullback Latrell Mitchell has missed the past three games through suspension.
Halfback Dean Hawkins suffered a quad injury against the Panthers, while Lachlan Ilias's season is all but over after his leg was broken playing reserve grade.
Winger Alex Johnston is at least due to return from a hamstring injury soon, with Souths taking on St George Illawarra and North Queensland in the next fortnight.
But the loss of Murray comes as another seismic blow to the Rabbitohs' faint hopes of rebuilding their season after one win from their opening eight games.