The Catholic Church in India had long felt the need of adding a Medical College to the many educational and social welfare institutions through which, over the years, it has served the country. However, the complexities such a venture involved, delayed its active consideration until 1942, when, on the initiative of the late Sister Mary of the Sacred Heart. M.D., of the Congregation of Jesus Mary and Joseph, the Catholic Hospitals Association of India was established, one of its principal aims being the opening of a medical college. The proposal was later pursued by the Catholic Bishops' Conference of India. The Secretary of the Conference, the late Archbishop of Bangalore, the Most. Rev. Thomas Pothacamury, took keen interest in it, and at the request of the Conference, the late Archbishop of Madras, the Most. Rev. Louis Mathias, S.D.B., prepared and presented a report in 1954, in which he reviewed the total requirements of the project. The subject was brought up before the Conference again inn 1956, and inn 1958. Archbishop Mathias undertook to formulate a specific scheme with the aid of medical and financial experts. He submitted the scheme to the Conference in 1956, and in September 1960, the Conference took the decision to establish the College, with an attached hospital, at Bangalore. His Holiness Pope John XXIII of revered memory, agreed to the college being called after his patron saint, as a mark of his personal interest in the project, and his approval of its aims and ideals. The College was accordingly named 'St. John's Medical College', and opened in temporary premises at Bangalore in July 1963. IN the course of their Joint Pastoral issued in connection with the XXXVIII International Eucharistic Congress, held in Bombay in 1964, the Catholic Bishops of India announced their choice of the College project as the Chief Memorial of the Congress. The choice received the warm approval of His Holiness Pope Paul VI, which was conveyed by him in a special message addressed to His Eminence Valerian Cardinal Gracias, the President of the Catholic Bishops' Conference of India, and President of the C.B.C.I. Society for Medical Education. His Holiness has also established a scholarship in the College in his own name, to be awarded, each year, to the best all-round student completing the M.B.B.S. Course.

The Corner Stone of the Project was blessed by His Holiness at Bombay during the principal function of the Congress, held on the 3rd December 1964, at which he officiated. It was laid at the Project site on the 27th July 1965 by His Excellency Shri. V.V. Giri, the then Governor of Karnataka, and later , President of India. On the completion of the buildings in the First Phase of the implementation of the Project, it was dedicated to the cause of Medical Education, Research and Care, on the 29th September 1968, at a ceremony presided over by the late President of India,. His Excellency Dr. Zakir Husain.

Prior to the completion of these buildings, the College was located in the premises of St. Mary's Industrial School, which were made available by His Grace the Archbishop of Bangalore, and in which provision was made for the teaching off pre-clinical and paraclinical subjects. St. Martha's Hospital where the clinical teaching of the College was mainly conducted had been extended and suitably equipped. In June 1968, five years after its establishment, the College moved to its permanent campus on a 160-acres site, situated about three miles from the centre of the city of Bangalore. The campus then consisted of buildings constructed during the First Phase, namely, the Teaching Centre, four Students' Hostel blocks, a Kitchen-and-Dining block, some Residences for the Teaching Staff, and a workshop. The construction work of the Second Phase consisted of a 750-bed Hospital and residences for the Resident Medical Staff and Nurses was started in 1971. The outpatients' Department and one wing of the Hospital Block was opened on Monday, 8th December 1975. The Campus Hospital then consisted of the Departments off General Medicine, General Surgery, Obstetrics and Gynecology, Pediatrics (Medical), and Thoracic Surgery. Soon the specialties of Cardiology including cardiac surgery, Nephrology and Genito-Surgery, Endocrinology, Dermatology and Venerology was to be added. Later, during the final Phase of the Project, it was proposed to provide a College of Nursing, a Dental College, a Convalescent Home, and a Rehabilitation Centre. Today, the College has a number of specialised departments, and also a number of operation theaters. Some of the Students who have passed out from St. John's Colleges as Doctors and Nurses, are employed in some of the most prestigious Institutions and Hospitals in the World.