Background Coronavirus disease (COVID-19) has emerged and spread rapidly worldwide and established a global public health crisis in early 2020. The first Moroccan case was reported on March 2, 2020. Since then, healthcare workers (HCWs) played a major role in saving human lives threatened by COVID-19. This study aimed to assess the prevalence of COVID-19 infection among Moroccan physicians and to report associated risk factors prior vaccination campaign. Methods A cross-sectional study was carried out in the Fez-Meknes region of Morocco, 545 physicians’ data was collected using a self-reported online questionnaire. The data collection was done between December 1, 2020, and February 1, 2021. Results The prevalence of COVID-19 among physicians was 27.3%. The mean age of the confirmed COVID-19 group was 38.4±12.9 years old. There was no association between COVID-19 infection and preventive measures compliance by physicians and healthcare authorities in the workplace. However, multivariate analysis strengthened the following factors such as increased risk of COVID-19 infection within men ☯aOR:1.896; 95% IC 1.272–2.828; p = 0.002]; the presence of at least one comorbidity ☯aOR:2.268; 95%IC 1.414–3.637; p = 0.001]; and working at a university or military hospitals ☯aOR:2.578; 95%IC 1.667–3.989; p = 0.001]. Conclusion This study allows comparing COVID-19 prevalence among healthcare workers before and after vaccination programs. This should support better preparation strategy for any future pandemics with appropriate and increased awareness for men, carrying comorbidity, and working environment with high COVID-19 disease management.