摘要:Background. Chronic stress among medical students affects academic performance of students and leads to depression, substance use, and suicide. There is, however, a shortage of such research evidence in Ethiopia. Objective. We aimed to estimate the prevalence and severity of stress and its association with substance use and academic performance among medical students. Methods. A cross-sectional survey was conducted on a sample of 329 medical students at Jimma University. Data were collected using the General Health Questionnaire (GHQ-12), Medical Students Stress Questionnaire (MSSQ-20), and Drug Abuse Surveillance Test (DAST). Data were analyzed using SPSS version 20.0. Logistic regression analysis and Student’s -test were applied. Results. The mean age of the respondents was 23.02 (SD = 2.074) years. The current prevalence of stress was 52.4%. Academic related stressor domain was the main source of stress among 281 (88.6%) students. Stress was significantly associated with khat chewing [AOR = 3.03, 95% CI (1.17, 7.85)], smoking [AOR = 4.55, 95% CI (1.05, 19.77)], and alcohol intake [AOR = 1.93, 95% CI (1.03, 3.60)]. The prevalence of stress was high during the initial three years of study. Stress was significantly () but negatively () correlated with academic achievement. Conclusion. Stress was a significant problem among medical students and had a negative impact on their academic performance. Year of study, income, and substance use were associated with stress. Counseling and awareness creation are recommended.