Psychoactive substance use is a major public health issue globally. Studies worldwide suggest that the prevalence of substance use among undergraduates may be on the rise. This study aimed at determining the prevalence, pattern and associated factors of substance use among students in a university in Southwestern Nigeria. The WHO Student Drug Use questionnaire was used to assess for drug use among final year students, while psychological distress was evaluated with GHQ 12. Lifetime prevalence of any psychoactive substance use was 78%. The prevalence of alcohol, cannabis and inhalant was significantly more in males. The prevalence of alcohol use was significantly lower among students who reported frequent participation in religious activities. There was a significant relationship between tobacco, cannabis use and psychological distress. The prevalence of psychoactive substance is high among university students. There is urgent need for adequate screening, assessment and treatment of substance use disorder amongst these students.