Jayne McGivern joined the Australian firm in 2005 from US entertainment group Anschutz as managing director of its developments arm.
She became CEO last September.
Just before Christmas, Multiplex was taken over by Canadian asset management firm Brookfield in a £3.4 billion deal and Ms McGivern has now exercised a change of control provision in her contract.
She will leave the firm on Friday.
James Tuckey, who stepped down last September as the firms UK chairman to take on the role part-time, has now returned to the full-time position.
He will report to Brookfield chief Bruce Flatt over in Toronto.
A Multiplex spokesman said: “We are very sorry to see her go. We wish her well for the future.”