Background: Mental distress is a group of mental problems manifested by symptoms of insomnia, fatigue, irritability, forgetfulness, difficulty in concentrating, and somatic complaints. University students have more severe mental health problems than the general population. Objectives: Therefore, this study attempted to assess the magnitude of mental distress and its determinants among medical and health science regular undergraduate students at Jimma University. Methods: A descriptive institutional-based with cross-sectional study design was conducted at Jimma University from March to April 2017 on regular undergraduate medical and health science students of the Faculty of Health Science. Study participants were selected from each batch using simple random sampling techniques and from the department by lottery method. Mental distress was assessed by using Self-Reporting questionnaire-20. Participants with score of eight and above on the Self-Reporting questionnaire-20 were considered as having mental distress. Chi-square and descriptive statistics were done using SPSS-20. Results: From a total of 369 study participants, about 354 gave the response rate of (95.9%). The magnitude of mental distress among medical and health science students was 35.03 %. Most of the respondents were males by sex and the mean age of the respondents was 23 years with SD ± 6. Age, sex, year of study, the practice of religion, presence of family history of mental illness, department choice, and ever use of substance (chat chewing and alcohol) were predictor variables and significantly associated with mental distress at P < 0.05. Conclusions: The magnitude of mental distress in our study was 35.03% and it needs intervention and addressing the mentioned factors significantly associated with mental distress.