Abstract Background and aim Health care workers (HCWs), mostly frontliners, are encountering numerous physical and psychosocial stressors, and even managing some conflicts over the course of the novel coronavirus disease 2019 (COVID-19). In this respect, the present study was to investigate the prevalence rate of occupational burnout (OB) in such workers during this pandemic. Materials and methods This cross-sectional study was conducted between April 6 and May 30, 2020, via an online survey in 31 provinces of Iran, on HCWs selected based on convenience sampling method. For data collection, a socio-demographic information form and the Maslach Burnout Inventory (MBI) was utilized. Descriptive statistics, Chi-square test, and multivariate regression analysis were also applied to test the research hypotheses. Results In total, 7626 HCWs participated in the present study. Accordingly, 73.2 and 26.8% of the workers were female and male, respectively. As well, 57.8% of the respondents were nurses and 14.4% of the cases were clinicians. Moreover, 44.8% of the participants had thus far worked in isolation wards and 40.3% of these individuals reported working for 4–8 hours with COVID-19 patients. The prevalence rate of OB was 18.3%. Besides, 34.2, 48.7, and 56.1% of the respondents had severe levels of emotional exhaustion (EE), higher depersonalization (DP), and decreased sense of personal accomplishment (PA), respectively. Besides, the HCWs at the age range of 20 to 30, having female gender, no children, and a bachelor’s degree, and working in isolation wards showed the higher levels of OB with reference to the Chi-square test results (p < 0.001). Accordingly, the statistical test outcomes demonstrated that a history of physical illnesses (p = 0.001) and psychiatric disorders (p = 0.044) could be the best predictor of OB throughout the first peak of the COVID-19 pandemic. Conclusion Regarding the high prevalence rate of OB among the HCWs and the remaining COVID-19 journey in Iran, health care managers are recommended to orient the required management and coping strategies toward improving mental health in these individuals.