BACKGROUND፡ Medical students often experience chronic stress. Self-esteem is one of the most important factors in the process of psychosocial growth and has remarkable effect on thoughts, feelings, values, and goals. The aim of this study was to assess the prevalence and associated factors of low self-esteem (LSE) and mental distress among Medical Students of Jimma University.METHOD: This cross-sectional study was conducted in Jimma University from June to July, 2018. Self-esteem was measured with Rosenberg self-esteem scale. Self-administered Short form with General Health Questionnaire was used to assess presence of mental distress.RESULT: Out of 422 students enrolled to the study, 279 (66.1%) were male, and 413 (97.9 %) were 18 to 25 years of age. The prevalence of LSE and mental distress were 19.0%, and 19.7 %, respectively. Students who had LSE had 5 times higher risk of having mental distress, AOR= 5.1 (95% CI, 2.9-8.9). Moreover, female students had higher risk of developing mental distress (AOR=1.9, 95% CI, 1.1-3.3). Students who had poor social support were 4.3 times at higher risk of developing LSE, AOR=4.3 (95% CI, 1.9-9.8). Those who reported to have poor academic performance were also more likely to have LSE AOR= 3.7 (95% CI, 1.3- 10.0).CONCLUSION: One in five medical students had LSE and it is strongly associated with metal distress. Female students were at higher risk of mental distress. Preventive, curative and rehabilitative mental health services should be available for medical students with particular attention to those with poor social support. KEYWORDS: Mental distress, low self-esteem, medical education