She married actor-manager Ben Webster in 1892 in St Giles's Parish Church, London, and in 1895 they visited the United States, where Whitty appeared on Broadway. Their first child, a son, died at birth. Their only surviving child, a daughter born in the USA in 1905, Margaret Webster, was a stage Actress and held dual US/UK citizenship. Whitty's stage career continued for the rest of her life. In March 1910, she made her transition to middle-aged and elderly character roles, playing Amelia Madras in Harley Granville-Barker's four-act comedy The Madras House. In March 1922, she played the role of Mrs. Bennet before the Queen in a benefit performance of Pride and Prejudice. She acted opposite her husband, who performed its Mr. Darcy.
In the 1918 New Year Honours, she was made a Dame Commander of the Order of the British Empire (DBE, gazetted under her legal married name Mary Louise Webster) in recognition of her charitable work during the First World War. She was the first film and stage Actress to receive a damehood, along with the opera singer Nellie Melba, who was also thus honoured in 1918.
She made her first major Hollywood film appearance recreating her stage role in the film Night Must Fall (1937), which also starred Robert Montgomery and Rosalind Russell, and received a nomination for an Academy Award for Best Supporting Actress. This led to several supporting roles in films, including that of the vanishing lady, Miss Froy, in Alfred Hitchcock's The Lady Vanishes (1938).
She moved permanently to the USA (although she never became a US citizen) in 1939 and appeared both on stage and in Hollywood films, usually playing wealthy dowagers. It was one such part, as Lady Beldon in Mrs. Miniver (1942), that brought her a second Academy Award nomination for Best Supporting Actress.