Aim <p>University students represent a high-risk group for licit and illicit substance use. Recent multisite data from Germany are scarce. This study aimed to examine associations between sociodemographic characteristics, mental health aspects, and substance use among university students in Germany.</p> Subject and methods <p>Data were derived from the Survey on Study Conditions and Mental Health of Students (StudiBiFra), including 21,651 students from eleven higher education institutions in Germany. It assessed alcohol and tobacco consumption and the use of illicit substances. Mental and physical health variables included general well-being, depressive symptoms, study-related anxiety, cognitive stress symptoms, exhaustion and physical symptoms. Multivariable and multinomial logistic regression models were applied to analyze associations between sociodemographic and mental and physical health variables and substance use.</p> Results <p>Monthly binge drinking was reported by 40.4% of students, and 22.4% reported smoking tobacco sometimes or daily. Cannabis use within the past 12&#xa0;months was reported by 20.1%, while other illicit substances were reported much less (1.4%-3.8%). Male students showed higher odds of using all substances. Financial difficulties were associated with increased substance use. Cognitive stress symptoms were associated with all substances, while study-related anxiety was linked to most substances except neuro-enhancers. Depressive symptoms were associated with tobacco use only. In contrast, exhaustion was associated with lower odds of using several substances.</p> Conclusion <p>Educational initiatives and targeted prevention programs for university students are essential, both to prevent the initiation of licit and illicit substance use and to support cessation among students who have already begun consuming these substances.</p>