Background: Identification of risk and protective factors is of great importance in designing preventive and interventional programs. The aim of the present study has been to investigate peer/individual, family, school, and community risk and protective factors as predictors of tobacco and alcohol use among Iranian adolescents. Methods: In a cross-sectional population-based study, 870 Iranian adolescents aged 15–18 years old, filled out the adopted form of “Communities That Care Youth Survey”. Thirty-two risk and protective factors were entered in adjusted logistic regression analyses to predict the lifetime cigarette and alcohol use. Results: Sixteen risk and seven protective factors predicted both lifetime cigarette and alcohol use in the bivariate logistic regression analysis. In the multivariate logistic regression analysis 12 risk factors including friends’ use of drugs, interaction with antisocial peers, sensation seeking, intention to use, perceived risks of drug use, family history of drug use, poor family management, parental attitudes favorable toward drug use, family conflict, academic failure, school low commitment, perceived availability of drugs predicted both lifetime cigarette and alcohol use as well as four protective factors including religiosity, self-esteem, family rewards for prosocial involvement, and school rewards for prosocial involvement. The highest OR were related to the risk factor of “Rewards for antisocial involvement” [3.9(1.5–10)], and protective factor of “Religiosity” [0.1(0.1–0.3)]. Conclusion: The present study has produced evidences about risk and protective factors related to adolescents substance use and can help designing and implementing of preventive interventions for maintaining and promoting adolescents health.