My Master Builder, a production by American playwright and screenwriter Lila Raicek, at Wyndham's Theatre is Scottish actor McGregor's first play on the London stage in 17 years.
Fleetwood will play Elena Solness, wife of architect Henry Solness (McGregor) - whose preparation for his party in the Hamptons is interrupted by Mathilde (Debicki).
The play has teased that Elena and Henry's "already vulnerable union is shattered by the unexpected arrival" of his former student.
Mathilde "shared an intimate connection" with Henry which sparks the three leads finding themselves "face to face with a reckoning that indelibly tilts the axis of their lives".
Trainspotting star McGregor previously worked with My Master Builder director Michael Grandage on productions of Othello and Guys And Dolls at Donmar Warehouse, where Grandage was artistic director.
Star Trek: Discovery actor David Ajala and The Witcher: Blood Origin actress Mirren Mack have also been announced for the cast as Ragnar and Kaja in the Henrik Ibsen-inspired play.
Debicki came to increased attention for playing Diana, Princess of Wales in Netflix royal drama The Crown for which she won a Golden Globe for best supporting actress, and was nominated for a BAFTA.
The Australian actress has also appeared in The Night Manager and time travel film Tenet, and acted at Britain's National Theatre in thriller The Red Barn.
* My Master Builder will run from April 29 until July 12 at Wyndham's Theatre.
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