Bitter Wheat is being written by the Pulitzer prize-winning David Mamet, who will also direct the production.
It will receive its world premiere in London's West End in June.
It is "a black farce about a very badly behaved media mogul," Malkovich told BBC News.
Scores of women accused Weinstein of rape or sexual assault, and the allegations led to what became the #MeToo movement.
Weinstein denies any claims of non-consensual sex and has described many allegations against him as "patently false".
More than 70 women have accused Harvey Weinstein of sexual misconduct
Malkovich, 65, says Harvey Weinstein was the "starting point" for the play and "a reaction to the all the news that came out last year" about him.
But it has subsequently developed and now explores how people of positions of power in the entertainment industry have behaved badly for decades.
Bitter Wheat, which will also star Doon Mackichan, is set in the present day and Malkovich plays Barney Fein, a depraved Hollywood producer.
"Of course it might upset people who've experienced the kind of treatment that the play contains and shows and describes," the former Oscar nominee says, adding: "A lot of people may not like it.
"But what can I do about that? Personally I think it's a terrific piece of writing."
Malkovich is best known for films including Dangerous Liaisons, Being John Malkovich, Con Air and Mulholland Falls.
The actor also gained a new audience of young fans over Christmas, as he starred in Netflix film Bird Box alongside Sandra Bullock.
He recently appeared on television playing Hercule Poirot in a new BBC Agatha Christie adaptation, The ABC Murders.
Malkovich plays Hercule Poirot in an adaptation of Agatha Christie's The ABC Murders
He says he "loved" doing it. But he is aware "it was a bit controversial and not appreciated in all quarters," and thinks that may make it unlikely that he would be asked to reprise the role.
Back in 1998, Malkovich co-starred in the film Rounders - which was financed by Weinstein.
But he says beyond that "I didn't really have any connection with him".
"They say everyone in Hollywood knew [about his behaviour].
"But that's not true - it was never a topic of conversation any time the name Harvey Weinstein came around with me."
Nonetheless, Malkovich says he hopes he is not "complicit" by being part of an industry which has allowed abuse of power to flourish unchallenged for years.
"Do I wish in retrospect I would have known a little more or said a little more?" he muses.
And although he thinks it is highly unlikely, he says it is not impossible that Harvey Weinstein could work in Hollywood again.
"It seems a long trip from where I'm sitting now, but nothing would surprise me about the movie business, nothing.
"One of the foundations of our society is the notion of redemption.
"It's a very tough topic. Could he be forgiven? That's not up to me. He didn't do anything to me. That's up to the individuals whose lives he affected."
Malkovich says its not impossible to think Harvey Weinstein could work in Hollywood again
Other casting has yet to be announced but Malkovich says one of Harvey Weinstein's accusers did ask to read the Bitter Wheat, with a view to appearing in it.
She later decided against it and he says he does not know why.
The author, director and playwright David Mamet is no stranger to the subject of sexual harassment allegations in his work.
In his play Oleanna, a student accuses her professor of misconduct. He has also written about Hollywood many times including Speed the Plow.
He has described Bitter Wheat as a comedy, which given the subject matter may surprise people. But Malkovich argues: "A lot of people will laugh.
"A lot of comedy for me exists at the crossroads between pain and farce," he says.
"In the end that's what theatre is for. A lot of great plays, done well, elicit the question do I laugh or do I cry?"
