Paxinou made her debut at the Municipal Theatre of Piraeus in 1920 in the operatic version of Maurice Maeterlinck's "Sister Beatrice", with a score by Dimitri Mitropoulos. She first appeared in a play in 1928, as a member of Marika Kotopouli's troupe, in an Athens production of Henry Bataille's "The Naked Woman". In 1931, she joined Aimilios Veakis' troupe along with Alexis Minotis, where she translated and appeared in the first of Eugene O'Neill's plays to be staged in Greece, "Desire Under the Elms". She also appeared in Anton Chekhov's "Uncle Vanya" and August Strindberg's "The Father".