Health Department boss Martin Bowles will exit the role next week after staff were told the veteran public servant would retire following a 40-year career.
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Mr Bowles, who took the helm at the department in 2014, will finish on September 1 ending a public service career spanning multiple departments.
Before heading up the Health Department, he led the Department of Immigration and Border Protection, and was deputy secretary at the Department of Climate Change and Energy.
He also worked at the Defence Department, where recently he was reportedly considered to succeed Dennis Richardson as secretary before Greg Moriarty, former chief-of-staff to Prime Minister Malcolm Turnbull, was appointed.
Mr Bowles' resignation will bring more change to the Health Department, where earlier this year he told staff 250 jobs would go through voluntary redundancies in a bid for savings amid federal budgetary constraints.
The announcement came after the departmental chief flagged last year that budget and staffing issues would be the department's largest challenges in 2017.
Mr Bowles oversaw other major changes at the Health Department, where he announced in 2015 to 3500 mostly Canberra-based staff a restructure that would not axe jobs, following a highly critical review the previous year.
He was a public servant for the Queensland and NSW governments before joining the Australian Public Service in 2006 to be Defence's deputy secretary.
Mr Bowles moved in 2010 to the Department of Climate Change and Energy Efficiency, where his work on energy efficiency policies and remediating the disastrous home insulation program was rewarded with the Public Service Medal two years later.
He was also part of an episode in the 2015 budget lock-up when budget papers were unavailable and Health Department public servants were unable to clarify changes, to the frustration of health professionals, but last year he praised his staff for a "180-degree turnaround" at the 2016 budget.
Health Minister Greg Hunt on Tuesday said Mr Bowles had a distinguished public service career and had driven change at the Health Department.
He noted Mr Bowles' work on an agreement with pharmaceutical body Medicines Australia for access to medicines.
"This is a significant reform which ensures that Australians have access to the world's best medicines with a sustainable Pharmaceutical Benefits Scheme," Mr Hunt said.
Prime Minister Malcolm Turnbull said the public servant had built a well-deserved reputation as a highly respected leader and driver of innovation.
Health Department deputy secretary Mark Cormack will be acting secretary while a successor for Mr Bowles is found.
Mr Bowles is the second departmental boss to announce his departure in one month, after Department of Environment and Energy secretary Gordon de Brouwer said he would quit in September "to pursue other interests".
