Mr Andrews will step down as the state's leader and as the member for Mulgrave effective 5pm on Wednesday.
"Nine years ago, I visited Government House to be sworn in as the 48th premier of Victoria - it has been the honour and privilege of my life," he told reporters.
"I'm also proud to think of all that we have achieved over these nine years in good times, and always working hard to do what's right, not simply what's popular."
He made the announcement at a snap press conference at state parliament on Tuesday with his wife Cath beside him.
"Recently in talking to my kids and Cath, thoughts of what life will be like after this job has started to creep in," Mr Andrews said.
"I have always known that the moment that happens, it is time to go and to give this privilege, this amazing responsibility to someone else.
"It is not an easy job being premier of our state, but that is not a complaint that is just fact.
"It requires 100 per cent from you and your family, that of course, is time-limited and now is the time to step away."
Mr Andrews became premier in November 2014, booting out a first-term Liberal government, and led Labor to two more victories in 2018 and 2022.
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