She debuted on the stage in 1888 (four years after she married Patrick Campbell), and her first notable role was as Paula Tanqueray in Sir Arthur Wing Pinero's play The Second Mrs. Tanqueray in 1893. Two years later she played Juliet to Sir Johnston Forbes-Robertson's Romeo and afterward appeared with him frequently. In 1907 she was a memorable Hedda Gabler in Henrik Ibsen's play of the same name and in 1914 played Eliza Doolittle in Pygmalion, a part her friend George Bernard Shaw wrote especially for her. In 1914 she remarried (her first husband having died in 1900), this time to Major George Frederick Myddleton Cornwallis-West.

She also achieved great success as Mélisande in Maurice Maeterlinck's Pelléas and Mélisande, Lady Macbeth in Macbeth, Mrs. Alving in Ibsen's Ghosts, Magda in Hermann Sudermann's Magda, Clytemnestra in Sophocles' Electra, and Anastasia in the play based on G.B. Stern's Matriarch in 1929. She made her film debut at the age of 68 in Riptide and subsequently appeared in several other motion pictures.

Her correspondence with Shaw, edited by Alan Dent, was published in 1952.