MacBride was born in Paris. He was the son of Major John MacBride and Maud Gonne. His first language was French but he was sent to school in County Wexford in Ireland. He joined the Irish Volunteers and was an active member of the War of Independence and supported the Republican side after the Treaty. MacBride was imprisoned several times and went on the run to London and Paris. He returned to Ireland in 1936 and became Chief of Staff of the IRA.
MacBride was called to the bar in 1937. He resigned from the IRA when Bunreacht na hÉireann (the Constitution of Ireland) was enacted later that year. As a barrister MacBride defended many IRA prisoners. In 1946 MacBride founded Clann na Poblachta which he hoped would replace Fianna Fáil as Éire's major political party. However in the 1948 general election the party failed to make the hoped for breakthrough. However the party joined with Fine Gael, Labour, National Labour, Clann na Poblachta and other parties and independents to form the First Inter-Party Government under Fine Gael TD John A. Costello. Two Clann na Poblachta TDs joined the cabinet; McBride became Minister for External Affairs while Noel Browne became Minister for Health. During his period in the government Ireland refused joining NATO but became a member of the Council of Europe. On Easter Monday, 18 April 1949, the Éire left the Commonwealth and the became the Republic of Ireland. MacBride controversially ordered Browne to resign as a minister over the controversial Mother and Child Scheme.
In 1951 Clann na Poblachta was reduced to two seats after the general election. MacBride kept his seat and was re-elected again in 1954. He contested both elections in 1957 and 1961 both failed to be elected. He then retired from politics and continued practising as a barrister. MacBride became increasingly concerned with human rights issues and the promotion of peace. He became a founder-member of Amnesty International and was international chairman from 1961-1974. That year he became president of the International Peace Bureau in Geneva.
In 1974 MacBride's work was recognised when he was awarded the Nobel Peace Prize. He later received the Lenin Peace Prize and the American Medal for Justice. He proposed a plan, known as the MacBride Principles, which he argued would eliminate discrimination against Catholics by employers in Northern Ireland and received widespread support for it in the United States and from Sinn Féin. However the MacBride Principles were criticised by the Irish and British Governments and most Northern Ireland parties, including the nationalist Social Democratic and Labour Party (SDLP), as unworkable and counterproductive.
Seán MacBride died in Dublin.