Background: Identification of the potential factors of depression among medical students is the first step towards academic excellence and future safe medical practice. Methods: A cross-sectional study was conducted during a period from November 2019 to February 2020 at the University of Bisha, College of Medicine (UBCOM), Bisha province, Saudi Arabia. Medical students from year one to year six were involved. A self-administered questionnaire was used to collect data about socio-demographic and academic characteristics of students. The Arabic version of the PHQ-9 scale with a score of ≥10 was used for diagnosis depressive. Logistic regression analysis was used to assess the prevalence and risk of depression.Results: Of the 190 students enrolled, 26.8% had depressive symptoms, of which 45.1% were having moderate to severe symptoms. The highest proportion of depression was found among second-year students (43.8%), followed by sixth-year students (41.2%), whereas lowest proportion of depression reported among first-year students (8.9%). Univariate regression revealed significant associations between depression and un-satisfaction of family income, loss of family members, having psychological illness, difficulties in personal relationships, regretted study medicine, failure in academic year, a lower grade than expected, conflict with tutors, lack of college facilities and heavy academic load. In multivariate analysis, loss of a family members (AOR=0.077; 95% CI 0.013-0.451), difficulties in personal relationships (AOR=2.371; 95% CI 1.009-5.575), regret study medicine (AOR=3.764; 95% CI 1.657-8.550), failed in academic year (AOR=2.559; 95% CI 1.112-5.887) were independently associated with depression.Conclusion: The study concluded that medical students at UBCOM also experience the existence of depressive symptoms associated with various risk indicators. Optimizing the educational and social environment coupled with infrastructure facilities at UBCOM might promote students' mental health and well-being.