Premier Peter Malinauskas on Thursday announced that Deputy Premier Susan Close and Treasurer Stephen Mullighan had stood aside from Cabinet and will retire from parliament at the March election.
He said he was "taken aback", "somewhat disappointed" and "really saddened" when he was approached separately by the ministers several weeks ago, and he had tried to talk them into staying.
"I'm here today to make it very clear that my persuasive powers failed, and they have both announced their resignation to our cabinet earlier today from cabinet and their intention to not contest the next state election," he said.
"I've known Susan and Stephen for a long time and they're good friends of mine and they've been incredible support to me in different ways over the last few years and I'm really sad to see them go," Mr Malinauskas said.
Dr Close, who was also the environment minister and a key figure in the government's response to the algal bloom disaster, has been deputy Labor leader since 2018.
She "wanted to do something else" and felt like she had "given what she can give" to public life, she said.
"Life is really short. I have been watching my mother disappear into dementia over the last four years," Dr Close said.
"And it was for me an alarm bell, reminding me that life is finite and it's precious."
Mr Mullighan, who was elected in 2014, has been treasurer since 2022 and also served as Minister for Defence and Space Industries, and Police Minister since January.
He said he wanted to be "more present as a husband and a father" to his wife and three children.
"I'm in a position where I've lost both my parents and (my wife) Antonia has lost her father," he said.
"It takes a village to raise children and our village is a little bit smaller. I want to make sure while the kids are still young, and I'm relatively young, that I can be around more and be more present."
Mr Malinauskas said the fact that "we've been able to keep this as a discreet internal exercise … speaks to the discipline of the unit".
"Which means we can plan for moments like this behind closed doors, with stability and thoughtfulness," he said.
The front bench that Labor will take to the election on March 21 will be announced on Friday.
Dr Close's seat of Port Adelaide and Mr Mullighan's seat of Lee are both Labor strongholds.
Labor is in a commanding position, holding 28 lower house seats compared to the Liberals' 13 seats in the 47-seat parliament.
In June, a YouGov poll showed Labor was on track to deliver the most decisive electoral victory in the state's history, securing 67 per cent of the two-party preferred vote.
In November, Labor won a by-election in the seat of Black after former Liberal leader David Speirs stepped down and was later convicted of supplying drugs.
Vincent Tarzia was selected as the new Liberal leader in August last year.
The YouGov poll showed Mr Malinauskas was leading Mr Tarzia 72-14 as preferred premier.
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