O'Donnell joins a list of actors - including Liza Minnelli and Jennifer Hudson - who will be appearing on the second season of the drama.
O'Donnell took to Twitter on Thursday (December 13) to announce the news, posting: "@NBCSmash - AND I AM SHOOTING A CAMEO TODAY ON SMASH !!!!!"
Smash was recently nominated for a Golden Globe in the 'Best Comedy or Musical Television Series' category.
The show stars Katharine McPhee, Megan Hilty, Debra Messing, Jack Davenport and Anjelica Huston.
Smash will return on February 5, 2013 at 9pm ET on NBC.
Watch a teaser for the second season of Smash below: