Scientific research on use and misuse of substances in Lebanon is scarce. This study aimed to evaluate the rate of use and abuse of substances among Lebanese youth and identify the determinants and risk factors behind these behaviours. An observational survey was conducted on 1945 university students selected from the different faculties of the Lebanese University and other private universities. A self-administered questionnaire based on ASSIST (Alcohol, Smoking and Substance Involvement Screening Test) was administered. The prevalence of ever consuming alcohol was 20.9%. Cannabis (12.3%) and tranquilizers (11%) had the highest rates of ever use among the drugs, whereas cocaine (3.3%) and hallucinogens (3.6%) had the lowest rates. Smoking cigarettes and waterpipes, going out at night, peer pressure and having no specific leisure time activity were associated with problematic substance use, while a better relationship with parents, reading and working were inversely associated with use. There is a high prevalence of substance use among university students in Lebanon. Multidisciplinary support for addicted students is needed to meet their diverse needs.