The current study examined the impact of supportive social relationships (i.e., teacher support, adult support, school relatedness) and peer victimization on middle school students’ substance use. Over 3,000 middle school students reported on alcohol, cigarette, and marijuana use, supportive social relationships, and instances in which they were the victim of aggressive behavior. Mixed-effects logit regression analyses revealed complementary patterns of results across types of substances. Students who perceived high levels of social support were less likely to report alcohol and drug use initiation, particularly at low levels of peer victimization. Gender moderated the negative effect of peer victimization, with highly victimized boys most likely to report alcohol, cigarette, and marijuana use. Results indicated a complex interplay of social influences and moderating variables in predicting early onset alcohol and other drug use, one that researchers should consider when studying adolescents’ decisions to use alcohol and other drugs.