Resilience as flexible response to the pressures of daily life acts differently based on gender. Therefore, it can have mediating role in relation to the effect of gender on substance use. This study aimed to examine the mediating role of resilience and tendency to addiction regarding the effect of gender on substance use. 300 university students (124 males and 176 females) were chosen by the convenience sampling method and they were evaluated by the resilience scale, the tendency to addiction questionnaire, and a researcher-made questionnaire about substance use. The results showed that there was a significant positive relationship between the tendency to addiction and substance use; there was a significant negative correlation between the tendency to addiction and resilience; there was a negative relationship between male gender and resilience; and there was a significant positive relationship between male gender and tendency to addiction. In addition, the proposed model fitted the data. Resilience has an important role in the prevention of substance use and those with high scores on resilience, despite a tendency to addiction, are less prone to substance use because of the ability to deal with difficult situations and flexible response to the pressures of daily life.