Malkovich will portray Hollywood studio head Barney Fein, who falls from grace in the production, which will run from June 7 to Sept. 14 at the Garrick Theatre in London.
Doon Mackichan, as Fein's assistant Sondra, and Ioanna Kimbook, making her theater debut, are also set to star.
Malkovich, while speaking with BBC Radio on Tuesday, said that while Mamet used the Weinstein scandal for inspiration, his character Fein is not exactly based on Weinstein.
"It's not particularly Harvey Weinstein. It's a great deal about that business and a great deal about how people in that business, in positions, say, as studio heads, have behaved really for more or less than a century now," the actor said.
"If the idea maybe started as a reaction to all the news that came out in particular about Harvey Weinstein, I think David took the idea from there and went with it."
Weinstein, the disgraced Hollywood production mogul, faces sexual assault charges in New York. Dozens of women have accused him of sexual misconduct.