: The COVID-19 pandemic imposed immense stress on healthcare systems worldwide, significantly affecting the mental well-being of healthcare workers (HCWs). This study examined the sociodemographic, occupational, and COVID-19-related predictors of burnout syndrome among Serbian HCWs. : A cross-sectional survey of 400 doctors and nurses utilized the Maslach Burnout Inventory to assess emotional exhaustion, depersonalization, and personal accomplishment. Sociodemographic, work-related, and COVID-19-related data were collected via a questionnaire. : Key predictors of emotional exhaustion included female gender, inadequate rest, sleep disturbances, and frontline COVID-19 work. Depersonalization was associated with fewer children, temporary employment, and COVID-19 frontline duties. Conversely, older age, religiosity, larger households, and a higher socioeconomic status positively correlated with personal accomplishment. : These findings emphasize the urgent need for targeted interventions, including improved working conditions and mental health support, to reduce burnout and enhance HCWs' well-being during medical crises.