ST Stanislaus' College head of college Dr Anne Wenham will retire from the position at the end of the school year.
Dr Wenham was appointed to the role in 2012, replacing long-serving headmaster John Edwards.
She was the first woman to be appointed to the role in the school's history, which dates back to 1867.
In a letter to the school community on Thursday, Vincentian Fathers Community provincial Father Gregory Brett said he accepted Dr Wenham's resignation "with mixed feelings".
"Some seven years ago she became the first female head of college. Since then she has given her all with unstinting energy," Father Gregory wrote.
"Her leadership and passion for the education of the students has been exceptional.
"The Vincentian community has appreciated the difficult context in which she took up her responsibilities. The college board respects and celebrates the many things she has accomplished."
Dr Wenham took over as head of college at a time when investigations were continuing into historic child sex charges at St Stanislaus' and a long list of former staff and priests were being brought before the courts.
As part of the college's healing process, Dr Wenham delivered a public apology in 2017 - the college's 150th year - to the victims of sexual abuse at the school.
"I express despair, horror, sadness and sorrow at the actions of some members of staff and I sincerely hope this apology is a step towards healing and we can begin to establish trust where trust was broken, establish hope where it was diminished and destroyed," Dr Wenham said at the time.
"I appreciate we cannot undo what has been done but ... we will continue to do all we can to make sure it never happens again."
In his letter to parents, Father Gregory said the search for a new head of college would "commence in coming days and months".
"Given the college's excellent reputation in the educational community locally and across the state, evident in such indicators as HSC results in recent years and strong commitment to social justice for a rural community, I am confident that the position will attract persons of the highest calibre," he said.