Objective: The present study aimed to investigate the mediating role of attitude toward substances in the relationship between critical thinking, media literacy, socialization, and propensity for substance use among adolescent girls in Isfahan. Method: This was a descriptive-correlational study using a structural equation modeling approach. A convenience sample of 300 adolescent girls aged 13 to 18 from the city of Isfahan was selected. The instruments used in this study included questionnaires to measure propensity for addiction, critical thinking skills, socialization, media literacy, and attitude toward addiction. Structural equation modeling with AMOS-24 software was used to analyze the research model. Results: The results showed that critical thinking had a significant direct effect on propensity for substance use. In addition, attitude toward substance use significantly mediated the links of of critical thinking and media literacy to propensity for addiction. Conclusion: According to the findings, by enhancing critical thinking and media literacy and consequently fostering a negative attitude toward substance use, it is possible to reduce the propensity for substance use in adolescents. Therefore, it is suggested that educational systems take steps to improve adolescents' critical thinking skills and media literacy to facilitate a change in their attitudes and propensity for substance use.