To maintain safety conditions in the provision of care and assistance, and to protect healthcare workers (HCWs) and patients, the Italian government required compulsory COVID-19 vaccination for HCWs, including medical residents (MRs). The aim of this study was to assess COVID-19 vaccination coverage in MRs in a large tertiary hospital in Italy, before and after the introduction of compulsory vaccination, according to demographic characteristics and specific residency. A database on COVID-19 vaccination status and infection of resident medical doctors was created. Descriptive statistics and logistic regressions were carried out on the data. A total of 1894 MRs were included in the study. Being vaccinated in the same hospital as the residency program was significantly related to the year of residency and being enrolled in a frontline residency. A significant association between compliance with the compulsory primary cycle vaccination and vaccination in the hospital residency was observed. Being enrolled in the second, third, and last years of residency, and in a frontline residency, were predictive of being vaccinated in the residency hospital. Almost 100% of the MRs participating in the study were vaccinated against COVID-19. Compulsory vaccination of HCWs, alongside greater and clearer information about the risks and benefits of vaccination, represents an important booster to ensure public health and to promote quality and safety of care.