In a statement posted to social media Mikakos said she had written to Victoria's Governor to resign as minister, and will also be resigning from the Parliament.
But she defended her handling of the pandemic, and said she disagreed with parts of Andrews' statement to the inquiry.
"I have never wanted to leave a job unfinished," she said.
"But in light of the Premier's statement to the board of inquiry and the fact that there are elements in it that I strongly disagree with, I believe that I cannot continue to serve in this Cabinet."
