St. Clare's, Oxford was founded in 1953 by Anne Dreydel OBE and Pamela Morris, and grew out of a scheme to establish links between British and European students after the Second World War. The original name was The Oxford English Centre for Foreign Students, which later became St. Clare's Hall, and then St. Clare's, Oxford. The College grew quickly to encompass a wide range of nationalities and programmes, both at university and pre-university level and in English Language. In the mid-50s, students came mostly from around a dozen Western European countries, as well as UK; nowadays there are over 40 nationalities represented on the IB programme alone!

As well as longer courses of study, shorter summer courses also became a central feature of the College in the early days.

Links with universities in the USA date back to the 1960s and formal agreements by which American university students could gain credit towards their US degrees by studying abroad at St. Clare's started up in the 1970s, and gradually replaced the University of London external degrees that had previously been taught.

In 1977 the College introduced the International Baccalaureate Diploma for pre-university students, only the 41st school in the world to do so, and currently the fourteenth longest established school in the world. "A" levels were gradually phased out as the IB became established and we are now the longest established IB school in England. Nowadays there are over 1500 IB schools in the world.

The College campus has grown with the increase in student numbers. From its original base in 141 Banbury Road, the College expanded to allow more teaching space and a wider range of subject choices, and early homestay arrangements were largely replaced with residential accommodation, as new houses in the area were acquired and refurbished. In 1999, the College bought the Oxford Academy site in Bardwell Road, which became the Senior Courses Bardwell Road Centre.

In 2003, St. Clare's Oxford celebrated its 50th anniversary with events in San Diego, Rio de Janeiro and in Oxford. A large number of St. Clare's 40,000+ former students still keep in touch and hold fond memories of their time here.