[3] 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.

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.

During her stay in the National Theatre, she distinguished herself on Greek stage starring in major plays, such as Sophocles' Electra, Henrik Ibsen's Ghosts and William Shakespeare's Hamlet, which were also performed in London, Frankfurt and Berlin.

Unable to return to Greece, she emigrated in May 1941 to the United States, where she had earlier appeared in 1931, performing Clytemnestra in a modern Greek version of Electra.

She was selected to play the role of Pilar in the film For Whom the Bell Tolls (1943), for which she won an Oscar and a Golden Globe Award for Best Supporting Actress - Motion Picture.

She played the lead in Ibsen's Hedda Gabler for 12 performances at New York City's Longacre Theatre, opening on 28 June 1942.