MacBride was the son of the Irish actress and patriot Maud Gonne (Gonne, Maud) and her husband, Major John MacBride, who was executed in 1916 for his part in the Easter Rising of that year against the British. Educated in Paris and Ireland, Seán MacBride, like his parents, was a fighter for Irish liberty and an opponent of the partition, and at age 24 he was chief of staff of the Irish Republican Army. He worked as a journalist and then became a lawyer.

Eventually accepting the fact of partition and the futility of warfare, he was elected to the Dáil Éireann (House of Representatives) in 1947 and remained until 1958 as a member of the Clann na Poblachta (“Republican Party”), which he had founded in 1936. He was minister for external affairs in 1948–51. In 1950 he was president of the Council of Foreign Ministers of the Council of Europe, and he was vice president of the Organisation for European Economic Co-operation in 1948–51. MacBride was active in a number of international organizations concerned with human rights, among them the International Prisoners of Conscience Fund (trustee) and Amnesty International (chairman, 1961–75), and he served as secretary-general of the International Commission of Jurists. In 1973 he became United Nations assistant secretary-general and commissioner for South West Africa/Namibia, posts he held until 1977. In 1977 he was appointed president of the International Commission for the Study of Communication Problems, set up by UNESCO.