Iain Cochrane will leave on 30 September after 20 years at the airport, five in his current role.
Chief commercial officer Graeme Sweenie will also go by the end of this month.
Chairman Andrew Miller said the changes are being made to implement a new “business model” at the loss-making airport which was bought by the government for £1 in November 2013. The government claimed it was a vital asset.
Mr Miller, a former head if Air New Zealand, said: “The future of Glasgow Prestwick is likely to be quite different from the past.
“The business model needs to be both re-designed and delivered rapidly so that the airport can look forward to a profitable, sustainable future. The board believes that this fundamental re-positioning requires new vision, leadership and expertise in the executive team.”
He said the search for a new chief executive and chief commercial officer was already under way.
Mr Cochrane said: “I’ve had twenty great years at Prestwick, five as chief executive. It has been my huge privilege to lead this fantastic airport with its exceptional and committed staff but it’s time for a change. I now look forward to a fresh challenge and exploring new opportunities.”
M Sweenie said he was “looking forward to a new challenge.”
The airport has relied heavily on Ryanair for passenger traffic, but has struggled to find a long-term sustainable model. It is short-listed as a potential space centre but that is by no means certain and is some years away.