It is the oldest and biggest of the four medical schools in Croatia (the other three being in Osijek, Rijeka and Split), having been established in 1917 and with 1,775 students enrolled as of 2008.

On 17 December 1917 the first professors' conference was held, and this date is officially celebrated as the school's day.

In the following years, the school significantly expanded its teaching staff, and a number of specialised clinics affiliated with the school were established, such as the clinics for internal medicine (1920), obstetrics and gynaecology (1920), neuropsychiatry (1921), otolaryngology (1921), pediatrics (1922), dermatology and venereal diseases (1922), orthopedics (1922), stomatology (1922), and an institute for radiology and occupational therapy (1922).

In the early 1980s, the school moved into their new central building in the Šalata neighborhood in northern Zagreb.

The building was officially opened on 25 May 1981, when Frano Kršinić's sculpture Girl Holding a Book (Djevojka s knjigom) was unveiled.