Introduction: Medical students are important and vulnerable populations. High levels of stress, financial dependency, easy access to substances, and lack of adequate support increase their mental health problems and substance use. In this study, we aimed to investigate the relationship between their mental health status and attitude toward substances. Methods: In this cross-sectional study, a total of 157 medical students were enrolled using the convenient sampling method, to answer the Drug Attitude Scale test and General Health Questionnaire. Data were analyzed using the SPSS. Results: Mental health is significantly correlated with the attitude toward substance use. The participants in this study had mental health problems in general. Half of them also had a positive attitude and tendency to use substances. Conclusion: Mental health problems and tendency to use the substances were prevalent among medical students. More investigations and designation of therapeutic and preventive programs are necessary especially for vulnerable populations.