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Rates of trauma exposure and post-traumatic stress disorder are higher in Indigenous, compared to non-Indigenous, populations and have been linked to substance use. Historical trauma is thought to be one mechanism underlying substance use and related disorders. The purpose of the present study is to summarize the current state of the literature focusing on the association between trauma (historical and lived) and substance use among Indigenous populations in the United States and Canada. Databases were systematically searched using the preferred reporting items for systematic reviews and meta-analyses statement. The search strategy initially yielded 4,026 articles. After exclusion of ineligible articles, 63 articles remained for synthesis. Results of the present review provide evidence for a positive link between substance use and both historical trauma (i.e., 86.4% of studies) and lived trauma (i.e., 84.7% of studies). Indigenous participants reported that historical trauma and pain related to loss of cultural identity contributed to substance use in their communities. Indigenous participants also consistently described an association between lived trauma and substance use. Despite heterogeneity among Indigenous communities, findings suggest a significant association between trauma and substance use across many different tribes and settings (e.g., reservation\/reserve, rural\/urban). Indigenous participants identified healing from trauma and reconnecting with culture as necessary components for reducing substance use and maintaining sobriety. 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