It was founded in 1846 by the 5th Nizam of Hyderabad and Berar, Afzal ud Dowla, Asaf Jah V. The college was originally affiliated to Osmania University system, now it is affiliated to the Kaloji Narayana Rao University of Health Sciences, and the Osmania General Hospital.

The college was established in 1846 and named the Hyderabad Medical School, during the reign of the 5th Nizam of Hyderabad - Afzal ad-Dawlah, Asaf Jah V.[6] When the Nizam became ill, probably from diabetes, the then British resident suggested he be treated with Western medicine by William Campbell Maclean.

[6] Edward Lawrie, then principal of Hyderabad Medical School, performed a series of experiments at the Afzal Gunj Hospital (now Osmania General Hospital) on anaesthesia[7] (Hyderabad Chloroform Commission).

[6] Rupa Bai Furdoonji, said to be the world's first qualified female anesthesiologist, graduated from the college in 1889.

[8] OSMECON is the chief Medical Conference (UG) hosted by OMC and its associated hospitals.