Background: Stress at workplace among health professionals predisposes to an inefficient organization, absenteeism from work, job dissatisfaction, and various physical, psychological as well as behavioral health problems. Despite this, little has been done into this health issue. So, this study assessed occupational stress and its determinants among health care professionals. Methods: Hospital-based cross-sectional study was implemented among 398 participants from May 1 to June 1, 2017, at Amanuel hospital, Addis Ababa, Ethiopia. A pretested and self-administered questionnaire was used to collect data. Nursing stress scale was used to assess occupational stress. Data was entered to Epi-info-version-7 and analyzed with SPSS-20. Descriptive statistics were also utilized. Binary logistic regressions with odds ratios and 95% confidence interval were used. P-value < 0.05 in final model was significant. Results: Among 398 participants included in the study, 393 provided complete information which gives a response rate of 98.7%. This study showed that 46.8% (95%CI: 41.7, 51.7) of health professional were having occupational stress. Multivariable binary logistic regression analysis showed that working in emergency department (AOR=3.48; 95% CI: 2.12, 12.08), forensic psychiatry unit (AOR=3.48; 95% CI: 1.25, 35.06) and job dissatisfaction (AOR=2.606; 95% CI: 1.563, 4.345) were risk factors for occupational stress. Conclusion Occupational stress among health professionals was high. Work-related variables (working in the emergency department and dissatisfaction with the job) were its risk factors. Attention has to be given for such an important public health issue.