BackgroundPsychoactive substance (PAS) use is a worldwide problem and has many health, sociological and economic effects. Several countries are alarmed by the growing incidence of drug use by students, and Ghana is no exception. Few studies have been carried out among students in Ghana. AimThis study assessed general PAS use, its association with psychological distress and possible risk factors among undergraduate students in a Ghanaian tertiary institution. MethodologyThe World Health Organization (WHO) students' drug use questionnaire and the General Health Questionnaire (GHQ-12) were used to gather information from a total of 400 students to evaluate the prevalence of PAS use and its association with psychological distress. The study employed proportion and chi-square or Fisher's Exact tests as well as logistic regression modelling in fitting models for factors of PAS use and psychological distress. ResultsThe mean age of participants was 21.66±2.19. Alcohol was the most (54.8 %) commonly used psychoactive substance. Students residing in university hostels (AOR=0.08; CI: 0.04, 0.16) and those who participate in regular religious activities (AOR=0.14; CI: 0.06, 0.28) were less likely to use any non-medical drug. Students who use alcoholic beverages (AOR=40.74; CI: 15.79, 121.87) and benzodiazepines (AOR=2.47; CI: 1.04, 5.93) were more likely to suffer psychological distress. ConclusionThere is significant psychoactive substance use among undergraduate students of the institution. The most frequently used substance in this research was alcohol, which followed the general trend. Residing on campus and engaging in regular religious activities were negatively correlated with the use of psychoactive substances.