O’’Donnell began her professional career as a stand-up comedian. She initially imitated Gilda Radner's famous character "Roseanne Rosannadanna" for a skit. That performance of her garnered her huge praise and helped developed a want in her to take forward her career in comedy. She watched and imitated other comics like Jerry Seinfeld and O'Donnell finally came up with her own idea and sharpened her captivating presence for the stage.
After the completion of her matriculation, she commenced on a stand-up comedy tour all around the US, featuring in 49 states and it went on for a period of more than five years. It was an enlightening and difficult time for O'Donnell, who slowly learned about the indisposed lifestyle and sexist climate that hovered around her during the tour.
After making appearances in various television specials, O'Donnell branched out to films. She made her silver screen debut with the film titled A League of Their Own directed by Penny Marshall.
She was mostly seen playing "best friend" parts such as Meg Ryan's closest friend in the film Sleepless in Seattle; pals of Emilio Estevez and Richard Dreyfuss in the film Another Stakeout and making an unforgettable appearance as the wise-cracking hairdresser in the film Beautiful Girls in 1996.
O'Donnell continued to climb the ladder of success on the small screen and most notable of them being her own daytime talk show and then by co-hosting the show named The View.