Abstract: The present quasi-experimental research aimed to investigate and determine the effectiveness of psycho-social empowerment on students’ general and behavioral attitudes towards drugs. The statistical sample consisted of 380 first-year high school adolescents who were chosen by multistage cluster sampling method. The experimental group was trained via 11 sessions that were conducted by police counselors and personnel. The data were collected using a drug attitude questionnaire. Then, the multi-way ANOVA was used. The results indicated that the scores of experimental group (in terms of cognitive and behavioral attitudes) were significantly lower than the scores of control group (p<0.01). Although, there was not any significant difference between male and female students in terms of behavioral attitude (p<0.05), they were significantly different in terms of general attitude (p<0.05). As a result, implementing the psycho-social empowerment program could increase students’ negative attitudes toward drug use. In addition, this training had a greater impact on female students in terms of general attitude towards drugs. Therefore, the introduction of interventions should consider the basic differences between the two genders.