In 1897 she married Robert Gould Shaw of Boston, from whom she was divorced in 1903, and in 1906 she married Waldorf Astor, great-great-grandson of John Jacob Astor. When her husband succeeded to his father's viscountcy and thus relinquished his seat in the House of Commons, Lady Astor, who had been his constant comrade-in-arms in his constituency at Plymouth, was adopted as Unionist candidate in his place and, after a stirring campaign, was elected by a substantial majority on November 28, 1919. Lady Astor was returned for Plymouth at subsequent general elections until her retirement from Parliament in 1945.

No less potent was her role as hostess at Cliveden, the Astor's country house near Taplow, Buckinghamshire, where she maintained a salon that exercised considerable influence in many fields, notably foreign affairs. Members of the group were called the “Cliveden set.”