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The purpose of the study was to examine potential moderators of the relation between two forms of victimization exposure (vicarious victimization of caretakers and dating violence victimization) and substance use disorders among 604 Indigenous (i.e., American Indian and Canadian First Nations) youth residing in the upper-Midwest and Canada. Drawing primarily from general strain theory, moderators were selected across developmental domains (i.e., community, family, peer, and individual). Community violence exposure, delinquent peer associations, and depressive symptoms were expected to amplify the hypothesized positive association between victimization exposure and substance use disorders, whereas family warmth and support was expected to buffer the association between victimization exposure and substance use disorders. Logistic regression analyses showed that family warmth and support buffered the association between vicarious victimization of caretakers and substance use disorders. Moreover, dating violence victimization amplified the effect of vicarious victimization of caretakers on substance use disorders. Although community violence exposure and delinquent peer associations were positively associated with substance use disorders, they did not operate as moderators. The results are contextualized for Indigenous communities and substance use prevention/intervention programming is discussed.