St Antony's was founded in 1950 as the result of the gift of Antonin Besse of Aden, a merchant of French descent. Its role was "to be a centre of advanced study and research in the fields of modern international history, philosophy, economics and politics and to provide an international centre within the University where graduate students from all over the world can live and work together in close contact with senior members of the University who are specialists in their fields".

The College opened its doors to its first students in Michaelmas Term 1950 and received its Royal Charter on 1st April 1953. A Supplementary Charter in 1962 was granted to allow the College to admit women as well as men and in 1963 the College was made a full member of the University.

The first Warden of the College was Sir William Deakin (1950-68), a young Oxford academic who in the Second World War became an adventurous soldier and aide to Winston Churchill. He won Antonin Besse's confidence and played the key role in turning his vision into the centre of excellence that St Antony's has become.

Sir Raymond Carr (1968-87), the second Warden and himself a distinguished historian of Spain, expanded the College and its regional coverage and opened its doors to visiting scholars from all over the world.

Sir Ralf (later Lord) Dahrendorf (1987-97) came to St Antony's after a distinguished career as a social theorist and politician in Germany, a European Commissioner and Director of the London School of Economics. He further enlarged the College and developed its role as a source of policy advice.

The fourth Warden, Sir Marrack Goulding (1997-2006), served in the British Diplomatic Service for 26 years before becoming an Under Secretary-General at the United Nations. His appointment underlined the international nature of the College and its links with government and business.

On the retirement of Sir Marrack, Professor Roger Goodman, a Fellow of the College since 1993, became Acting Warden in October 2006.

The College's fifth Warden, Professor Margaret MacMillan, took office in July 2007. Before becoming Warden she was Provost of Trinity College and professor of History at the University of Toronto, and she was a student at the College. She has published extensively. Her recent publications include Peacemakers: the Paris Conference of 1919 and Its Attempt to Make Peace (2002); When Nixon met Mao (2006); The Uses and Abuses of History (2009); The War that Ended Peace (2013); History’s People: Personality and History (2015).

The College's sixth Warden, Professor Roger Goodman, took office in October 2017. His relationship with the College began in 1982 when he arrived to start his doctoral work in social anthropology. Roger is an anthropologist by training and has been Nissan Professor of Modern Japanese Studies at the University of Oxford since 2003. He was the inaugural Head of the newly-created Oxford School of Interdisciplinary Area Studies between 2004-7 and then Head of the University of Oxford's Social Sciences Division for almost ten years and a member of the University's ruling Council for eleven years before taking up his post as Warden at St Antony's College. He has published widely on many aspects of Japanese education and social welfare institutions and his most recent book is a monograph on the changes that are taking place in Japanese higher education.  He is a Fellow of the UK Academy of Social Sciences and was President and the Chair of the Academy's Council between 2015-21.

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