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This study aimed to identify risk and protective factors associated with substance use among Iranian university students. We searched for studies in English published from January 1, 1995 to February 20, 2021, on PubMed, Scopus, Cochrane, and Web of Science to identify primary studies on the factors associated with substance use among university students. Out of 8,481 articles, 39 studies met eligibility criteria. Our findings showed a pooled prevalence rate of alcohol use 23% (95% CI, 8% 39%), smoking 21% (95% CI, 6% 37%) and other drug use 14% (95% CI, 10% 18%) in the last year among student. Hookah use, living alone, being a current cigarette smoker, and other drug use were significantly associated with alcohol use. The findings of the present study showed that being male, older age, alcohol use, had depression, had parents or friends who smoke, and religious beliefs were significantly associated with smoking among students. This meta-analysis also showed that living alone, alcohol use, history of drug use, and hookah use were significantly associated with drug use among students. Substance use prevention programs provided by universities could be improved by signifying high-risk populations addressed by the related literature. [ABSTRACT FROM AUTHOR]