BACKGROUND: Although mental health problems affect the general population, students are highly vulnerable to psychological disorders. Mental distress among students is a cause of concern as it may impair their behavior and diminish learning, which could negatively affect their academic performance. Therefore, the objective of this study was to assess the prevalence and the factors associated with mental distress among college students in Southern Ethiopia.METHODS: Institution based cross-sectional study was conducted among 280 regular students of Hawassa College of Health Sciences. Mental distress was measured using a Self-Reporting Questionnaire (SRQ-20). The data were entered into Epi-Info version 3.5.4 and analyzed using Statistical Package for Social Science (SPSS) version 20. Multivariable logistic analysis was performed following bivariate analysis to adjust for the effect of confounders.RESULT: The prevalence of mental distress among the study subjects was found to be 59 (22.30%). Female students were 2.08 times more likely to have mental distress as compared to male students (AOR =2.08 [95% CI: 1.14-3.82]). The odds of mental distress among third-year students was 60% lower compared to second-year students [AOR = 0.40; 95 % CI, (0.19, 0.87)]. Students who were from Amhara ethnic group were 3.37 times more likely to have mental distress as compared to students from Sidama ethnic group [AOR=3.37;95%CI (1.13-10.09)]. Moreover, students who had Grade Point Average of below 60% were 4.69 times more likely to be mentally distressed as compared to those students who scored Grade Point Average of greater or equal to 60% (AOR= 4.69; 95%CI,[ 2.46, 8.96).CONCLUSION: The finding suggests the importance of providing mental health counseling support for students as part of the teaching and learning process. More research to further explore the multiple factors influencing students’ mental health condition should also be conducted.