In 1913, Oliver Morosco cast her as Queen Ann Soforth of Oogaboo late in the run of L. Frank Baum and Louis F. Gottschalk's The Tik-Tok Man of Oz (better known in its novelization as Tik-Tok of Oz). In 1916, Morosco commissioned a successful star vehicle stage play titled So Long Letty. In 1919 Morosco brought her back in the sequel Linger Longer Letty. This role made her a star; she reprised it in the 1929 movie of the same name.
Greenwood had her own radio program, The Charlotte Greenwood Show, a situation comedy. It was broadcast 1944-1946, first on ABC and later on NBC. She also was in "Home in Indiana" on Lux Radio Theatre October 2, 1944.
She appeared with such luminaries as Charles Ruggles, Betty Grable, Jimmy Durante, Eddie Cantor, Buster Keaton, and Carmen Miranda. Most of Greenwood's best work was done on the stage, and was lauded by such critics as James Agate, Alexander Woollcott, and Claudia Cassidy. One of her most successful roles was that of Juno in Cole Porter's Out of This World in which she introduced the Porter classic "I Sleep Easier Now". She had some discomforts with that play, as she had become a devout Christian Scientist and feared the play was too risqué. One of her last movie roles was singing and dancing as the feisty matriarch, Aunt Eller, in the film adaptation of Rodgers and Hammerstein's Oklahoma! (1955).