The college was inaugurated on 2 August 1954 by the then chief minister K. Kamaraj and the union health minister Rajkumari Amrit Kaur. K. P. Sarathy was the first special officer, and Sarah J. Sowri was the first principal. The college was affiliated with the University of Madras, and permanent recognition was accorded in 1954. Subsequently, the recognition of the Medical Council of India (now the National Medical Commission) came in 1961.

The college was then situated at the old Taluk building, Fair Weather Road. The present building was occupied in 1958. In 1963, Dr. C. K. Padmanabha Menon became its first dean. It celebrated the Silver Jubilee in 1979 and Golden Jubilee in 2004.

When the Madurai Kamaraj University was established, the college was affiliated with it. When the Tamil Nadu Dr. M.G.R. Medical University was started, the college, like other medical colleges in the state, was affiliated with it.

The hospital was established in 1842 and became a teaching hospital in 1954. The hospital was formerly known as Erskine's Hospital.

Madurai Medical College is affiliated to Tamil Nadu Dr. M.G.R. Medical University and is recognised by the World Health Organization. It is most busiest hospital in state of Tamil Nadu, and it is also the only hospital in the State to have doctors available 24x7 in all speciality departments.

The hospital is not only centre of excellence in Southern Tamil Nadu but also in the State for various surgeries. It serves as a tertiary level referral hospital to all the medical college Hospitals of Southern and Central Tamil Nadu. Open heart and closed heart surgeries and valve replacement are performed in this hospital. Master Health Check-up is available. This hospital provides a 24 hours casualty facility, 24 hours bio-chemistry lab facility, CT Scan and MRI scan facilities, and so on. It provides tertiary care with the comprehensive health insurance scheme by the government of Tamil Nadu