Adolescent substance use research has yet to consider victimization as a potential risk factor contributing to alcohol and marijuana use among American Indian youth living on or near reservations, despite the presence of traumatic experiences, childhood adverse events, racism, and discrimination. Contribution to this lack of attention may be due to little being known about American Indian youth victimization. Even less is known about its association with alcohol and marijuana use in general and for those youth living on or near reservations in particular. This study utilizes mixed methods with a nationally representative sample of American Indian youth living on or near reservations in the first phase. A qualitative study in the second phase followed up with a group of practitioners serving American Indian youth living on or near a reservation to explore the association between victimization and alcohol and marijuana use. Understanding the perceptions of practitioners presents an opportunity for collaborative knowledge creation on the conceptualization of victimization and its relationship to alcohol and marijuana use. A secondary data analysis utilizing ordinary least squares regression yielded several significant contributions to alcohol and marijuana user levels when the models were run with the sample intact and when run by gender and compared side-by-side. Extending these findings to a qualitative follow-up produced themes that illustrated practitioner conceptualizations of victimization and perceptions about the influence of these experiences on alcohol and marijuana use among the American Indian youth they serve. Study findings inform or enhance substance use treatment design, delivery, and policy, and to advocate for tribal sovereignty and self-determination.