Background: Mental distress is a major public health problem which includes anxiety, depression and somatic symptoms such as sleeping problems, fatigue and headache. University students are consistently reported to have higher levels of mental distress compared to the general population. Although university students with mental distress have significantly impaired cognitive functioning, learning disabilities and poor academic performance, the burden of this problem in Tanzania is unknown. This study aimed to determine prevalence and factors associated with mental distress among undergraduate students in northern Tanzania. Methods: A cross-sectional study was conducted among undergraduate students at Kilimanjaro Christian Medical University College from April-July 2018. Simple random sampling technique using probability proportional to size was used to sample students from their respective classes. Mental distress was screened using the self-reporting questionnaire (SRQ-20). Data was analyzed using Stata version 15.1. Frequencies and percentages were used to summarize categorical variables while mean and standard deviation for numeric variables. Multivariable logistic regression was used to determine factors associated with mental distress adjusted for potential confounders. Results: A total of 402 undergraduate students participated in this study, 14% screened positive for mental distress. Residing off-campus (OR = 0.44, 95%CI 0.20-0.96) and perceived availability of social support (OR = 0.22, 95%CI 0.11-0.45) reduced the odds of mental distress while students with family history of mental distress (OR = 2.60, 95%CI 1.04-6.57) and those with decreased grades than anticipated (OR = 3.61, 95%CI 1.91-6.83) had higher likelihood of mental distress. Conclusion: One in every ten students screened was positive for mental distress. Those who reported a family history of mental illness and lower grades than anticipated had higher response of mental distress. To relieve students from stress and frustrations related to studies and their lives in general, this study recommends awareness creation, counselling to help those with mental health issues, establishment of student drop-in centers for such services and promotion of social and recreational activities at the college.