In what looms as a brutal double blow for the Rabbitohs, Murray suffered a suspected achilles tendon rupture at training before Mitchell's issue.
South Sydney officials confirmed they expected their representative lock to be sidelined for several months, depending on the severity of the injury.
Ruptured achilles can rule players out for up to eight months, although others have been able to return up to three months earlier.
Mitchell was then also hurt at the same session, ruling him out of at least Saturday's Charity Shield fixture against St George Illawarra in Mudgee.
The superstar No.1 was also to undergo scans, set to determine whether he will be fit to start the regular season.
Mitchell has had hamstring issues in the past, including during both the 2020 and 2022 seasons.
He then managed only 11 games last year, sidelined for the second half of it with a foot issue as the Rabbitohs missed the finals for a second straight season.
The injuries are the latest in a tough start to coach Wayne Bennett's return to the Rabbitohs this season.
Campbell Graham (hand) and five-eighth Cody Walker (calf) are both under an injury cloud ahead of the round-one clash with the Dolphins on March 7.
Flyer Alex Johnston has his own achilles issues, and is expected to miss at least the first month of the season as he battles to return.
For Murray, his suspected achilles injury continues a horror run of bad luck.
He missed part of last season with a hip injury, before suffering damage to his wrist while in end-of-season Kangaroos camp.
The Rabbitohs captain was then in a race against the clock to face the Dolphins in round one on March 7, with the wrist problem having lingered longer than expected.
That now appears the least of his concerns.
Murray spoke only last week about trying to put the Rabbitohs' long run of injuries out of his mind, after club-wide injuries stunted their 2023 and 2024 campaigns.
"I try not to think too much about it, because if you think too much about it you just drive yourself crazy," Murray told AAP at last Monday's NRL season launch.
"We have had enough time over-thinking things, victimising ourselves.
"The only way to get over something like that is just control what you can.
"If you are unlucky enough to pick up an injury just deal with what you need to do with your rehab to get back out there.
"You can say: 'Why is this happening to us?'. Or you can say: 'This is happening to us, how do we come back from it?'."
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