The "When Harry Met Sally" star will play veteran comedian Buddy Young, Jr. in the production - a revamp of the film, with which Billy made his directorial debut.
"Creating and portraying the 75-year-old comedian Buddy Young Jr. in the film of Mr. Saturday Night was one of the highlights of my career," Crystal said in a statement. "30 years ago I needed 5 hours of make-up to play him, now I just show up."
"Mr. Saturday Night" will begin performances on 1 March (22) at the Nederlander Theatre, with an official opening night on 31 March.
Crystal will be joined onstage by Randy Graff and David Paymer, who will reprise his Oscar-nominated role as Buddy's brother Stan Yankelman.
The musical will feature a score by three-time Tony Award winner Jason Robert Brown and lyrics by Amanda Green, while Crystal will create the book with Lowell Ganz and Babaloo Mandel. John Rando will direct.
"It's been a joy to collaborate once again with the brilliant and hilarious Lowell Ganz and Babaloo Mandel, my co-writers from the film, and to be joined by the wonderful team of Jason Robert Brown, Amanda Green, (choreographer) Ellenore Scott and John Rando," Crystal adds. "And it doesn't get any better than sharing a stage with Randy Graff, my old friend David Paymer, and Chasten Harmon."
"Together we have created a truly funny and moving musical comedy. I can't wait to come back to Broadway next year at the Nederlander Theatre."
Crystal was last on Broadway for his Tony Award-winning solo show "700 Sundays" in 2013.