BACKGROUND: The American Indian/Alaskan Native (AI/AN) mortality rate from illicit drug use was 22.7%, double that of the general population between 2007 and 2009. Fifteen percent of AI/AN youth reported receiving treatment for substance use compared with 10% of non-AI/AN peers. OBJECTIVE: The purpose was to explore the factors that influence substance use among AI/AN youth. METHOD: We performed a systematic review using a results-based convergent synthesis design. Eight electronic databases were searched for articles published between 2014 and 2019 using the search terms “Native American youth,” “Native American adolescent,” “Native Youth,” “substance use,” “substance misuse,” and “substance abuse.” The Mixed Methods Appraisal Tool was used to appraise the studies. RESULTS: Forty-seven studies met the inclusion criteria (44 quantitative, one qualitative, and two mixed-methods studies). The results were organized using the ecological systems model and included evaluation of both protective and risk factors related to AI/AN youth substance use. Three system levels were found to influence substance use: individual, micro- and macrosystems. The individual systems-level coping mechanisms played a key role in whether AI/AN youth initiated substance use. Family, school, and peer factors influence the microsystem level. At the macrosystem level, community environmental factors were influential. CONCLUSION: The major factor linking all the systems was the influence of a connected relationship with a prosocial adult who instilled future aspirations and a positive cultural identity. Findings of this systematic mixed studies review will assist in intervention development for AI/AN youth to prevent substance misuse.