The Batman Begins actress will appear in Smash co-creator Theresa Rebeck's new play Dead Accounts.
Rebeck told The Wrap: "It's beyond cool, honestly. The whole team is lively as hell. I am positively tingling with delight."
Dead Accounts is a comedy about a man who unexpectedly returns home to Cincinnati without his wife in tow, but with a large sum of money to hand.
Holmes is tipped to play the protagonist's sister Laura.
Further details, including further cast members and an opening date for the production, are due to be announced soon.
Holmes made her Broadway debut in 2008, appearing in a revival of the Arthur Miller play All My Sons.
She recently agreed a divorce settlement with former husband Tom Cruise, including a joint custody agreement for their 6-year-old daughter Suri.
Rebeck stepped down as showrunner on Smash earlier this year, but will remain on the NBC drama as an executive producer.
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