Objective: College students are at an increased risk of mental distress. The purpose of this study was to determine whether mental and lifestyle factors differed according to self-reported levels of psychological distress. Design and setting: A self-report questionnaire comprising the Kessler-6 Psychological Distress Scale, Revised Life Orientation Test, Rosenberg Self-Esteem Scale, Multidimensional Scale of Perceived Social Support and 24-hour recall of lifestyle behaviours was administered to 195 undergraduate college students at a Midwestern US university. Methods: Respondents were grouped into categories of low, moderate and severe mental distress using established cut-points for the Kessler-6 Psychological Distress Scale. Between-group differences were assessed to determine whether the mental and lifestyle variables under investigation differed according to magnitude of mental distress. Results: Significant differences were found between the three categories of mental distress and amounts of optimism, self-esteem and social support. Analysis of the lifestyle variables suggested groups were different for behaviours pertaining to computer screen time, fruit consumption and sugar-sweetened beverage intake when categorised into the three-tier groupings. No significant differences were found for the remaining lifestyle variables or for body mass index. Regression analysis found low levels of optimism, self-esteem and social support significantly predicted mental distress. Conclusion: Results of this study suggested higher amounts of optimism, self-esteem and social support were associated with decreased levels of mental distress in a sample of college students. Additional research is required to determine the role of lifestyle variables in mental distress.