The history of Medical College starts with construction of Sree Avittom Thirunal hospital for women and children by Travancore Royal Family.

His death due rheumatic heart disease lead then Maharaja Sree Padmanabha dasa chithira thirunal balarama verma to construct this unique first few of its kind in India.

The campus was 139 acres (0.56 km2), with hillocks surrounded by evergreen coconut groves and paddy fields and facing the sea, 4 kilometres (2.5 mi) from northwestern Thiruvananthapuram city.

The college and hospital buildings were separated by playgrounds for football and hockey, a cricket pitch, courts for tennis, basketball, badminton and volleyball, and a 400-meter track.

The foundation stone was laid by Raja Pramukh of Travancore–Cochin (Sree Padmanabhadasa Vanchipala Chithira thirunal Balarama Verma) at 11:45 am on 26 January 1950, and the first group of students was admitted in August 1951.

The block was funded by the prime minister's Swasthya Suraksha Yojna scheme and by the Kerala government.

Recognizing the importance of the new specialty of orthopedic surgery, the government of Travancore sent K. I. George of the health services department to the UK for advanced training.

The department of physical medicine and rehabilitation, established in 1968, pioneered disability management and the treatment of occupational diseases in India.

The hospital averages 55 major and 125 minor operations and 35 vaginal deliveries and 15 caesarean sections per day.

A primary health centre, founded in July 1953 in Cheruvikkal for field practice, was moved to Pangappara in 1964.

It was built by the Travancore royal family in memory of Prince Sree Avittom Thirunal, who died at age eight years of rheumatic heart disease.

The OB-GYN department administers the postpartum, family-welfare counseling, infertility, trophoblastic, adolescent and vesicular-mole clinics and WHO and Indian Council of Medical Research collaborative study centers.

The hospital also provides pediatric care in cardiology, neurology, nephrology, genetics, surgery and psychiatry, and has one of Asia's highest delivery rates.

Cadaver organ retrieval and transplant began in 2012, making it the first government hospital to offer the service on a wide scale.

The Child Development Centre was established by the government of Kerala for early-child and adolescent care and education, premarital counselling, women's welfare and related fields.

Other facilities are toxicology and animal labs, a drug-information center, morphine-tablet manufacturing and a medicinal The college, founded in 1972, is affiliated with the University of Kerala medical school.

It is headed by physiatrists who conduct the daily OP clinics and also attend to the ward patients as well as OP/IP consultations from other departments.

The investigative facilities available at the department includes urodynamics, instrumented gait analysis, electrodiagnostics (nerve conduction study, electromyogram), musculoskeletal ultrasonography, pulmonary function tests etc.

The physiatrist draws up a rehabilitation program to address the felt needs of the patient and ultimately to improve the functional status to maximum possible extent.

The physiatrist uses medications, exercises, semi invasive interventions and surgeries to improve the quality of life of the patient.

Also for the in-patients, the physiatrist looks after the general medical issues/co-morbidities like diabetes, hypertension as well as the specific complications encountered in rehabilitation period like pain, pressure sore, DVT, spasticity, contractures, nutritional issues (anemia, hypoproteinemia etc).

The library, housed in the administrative wing, contains books and academic journals relating to medicine and its allied sciences.

Its Learning Resource Center (LRC), established by the college's alumni association, has internet-enabled computers for paid use and subscribes to online medical journals A state of the art platform for motivating medical fraternity and students in multidisciplinary research activities.

The college conducted an international Erudite Conclave, the region's first, in November 2011 to provide momentum to medical research.

Speakers included Nobel laureate in medicine Rolf M. Zinkernagel, ophthalmologist and inventor of inexpensive intraocular lenses Sanduk Ruit, and SRISTI and techpedia.in founder Anil Kumar Gupta.

Visitors have included Alexander Fleming, E. Lundsgaard, Karl Evang, Julian Huxley, Wharton Young, Jean Aicardi, David Morley and A. Lakshmana Swamy Mudaliar.

Annual cultural events (organised by the classes) and sports and games competitions are held on campus.

During the annual Interbatch Euphoria, students from different batches compete in the fields of arts, cultural activities, quizzes and sports.

On June 15, 2024, a 59-year-old man named Ravindran Nair was rescued after being trapped for two days in a lift at the Government Medical College Hospital in Thiruvananthapuram.

Despite pressing the alarm and trying emergency numbers, no one responded until a lift operator discovered him during routine work on Monday.