Objective: Addiction is a chronic disease that is characterized by impaired individual, physiological, and social functioning. Wisdom and self-transcendence, as protective factors, can be effective in predicting tendency to substance use. This study aimed to investigate the relationship of wisdom and self-transcendence with the tendency to substance use among university students. Method: A descriptive correlational research method was used in this study. In this study, students of Azarbaijan Shahid Madani University constituted the statistical population where a 361-participant sample was selected using multi-stage cluster sampling method. Three-Dimensional Wisdom Scale (3D-WS), Adult Self-Transcendence Inventory (ASTI), and drug use tendency questionnaire were used for the purpose of data collection. The data were analyzed via Pearson correlation coefficient and multiple regression analysis methods. Results: The results showed that there is a significant relationship between components of predictor variables and tendency to substance use. Moreover, it was revealed that wisdom and self-transcendence can predict and explain variance of tendency to substance use (P<0.01). Conclusion: Since wisdom and self-transcendence can predict and explain variance of tendency to substance use, it is possible to reduce the rate of tendency to substance use by nurturing and promoting such characteristics.