Background: Mental health of students deteriorate when they begin studies in a medical school and remains poor throughout the period of training. Notwithstanding that medical students of today are the physicians of tomorrow who need to have stable mental health for effective performance, mental status of this group have not been adequately explored in the Nigeria context. The study aimed to determine the prevalence of depression and associated factors among medical students in Nigeria. Methods: A cross-sectional study was carried out on all matriculated medical students of Ebonyi state University Abakaliki, Nigeria. Information was obtained from 522 medical students that were eligible to participate in the study using self-administered structured questionnaire. Becks Depression Inventory was used to determine the prevalence of depression. Chi square test was used in the analysis to ascertain association between variables. Level of statistical significance was determined by a p value of <0.05.Results: Mean age of the students was 23.2±3.3 years and majority, 60.2% were males. Prevalence of depression was 17.4%. Third-year class (major examination class) had the highest proportion of students who were depressed, 24.2% while final year class had the least, 8.8%. Coping mechanisms for low moods included sleeping, 50.4% and having interactions with colleagues, 46.9%. Factors associated with depression included being <25 years, (p=0.008), being in clinical school, (p=0.023) and being afraid some students may not graduate from medical school, (p=0.030).Conclusions: Burden of depression was high among the students and most pronounced among third year students. There is need for proper orientation of newly admitted medical students on the medical curriculum by authorities of the university. Medical students preparing for major examinations should be well supported and encouraged by their colleagues and efforts should be made to decrease undue anxiety among the students. Adequate measures should be put in place for early detection and prompt management of cases of depression among the students.