BACKGROUND Due to exhaustive working climate, health-care professionals (HCPs) are highly exposed to emotional strain and work-related stress that leads to burnout syndrome (BOS). OBJECTIVE We aimed to explore the prevalence of BOS among HCPs and delineate the factors that contribute to developing this emerging threat in HCPs working in Gondar University Hospital (GUH). METHODS A cross-sectional study was conducted among HCPs using a self-administered validated questionnaire containing sociodemographic and job characteristics, symptoms of burnout using Astudillo and Mendinueta questionnaire, and Maslach Burnout Inventory scale. The prevalence of BOS was assessed by summation of answers to all 19 items with a range of 0-57. HCPs who scored >23 were considered as burned out. Pearson's correlation analysis and multivariate logistic regression were used to assess the relationship between BOS and job factors. Data were analyzed using descriptive and inferential statistics. RESULTS A total of 250 HCPs were approached out of which 248 responded (response rate -99.2%). The overall prevalence of burnout was 13.7% and majority of the respondents experienced debility (52.8%), self-criticism (56%), and depressive symptoms (46%). BOS symptoms were significant with age (P = 0.008), number of patients treated per day (P < 0.001), and HCPs working in shifts (P < 0.001). Higher mean levels of emotional exhaustion (5.4 ± 1.2) and inefficacy (5.1 ± 1.7) were noticed than cynicism (4.8 ± 2.0). Male HCPs, being single and years of experience, were determinant factors for all the three dimensions of BOS, whereas profession was significantly determinant for emotional exhaustion (P < 0.01). CONCLUSIONS The prevalence of BOS among HCPs working in GUH was 13.7%. Being male, unmarried, and years of experience were significant risk factors for all the three dimensions of BOS. Pragmatic measures are recommended to prevent stressful challenges for the physical and mental well-being of the HCPs in GUH.