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Prescription drug misuse (PDM) has become a major health issue in the U.S. over the past decade. PDM affects all ethnic and racial groups; however, there is a higher prevalence among American Indian (AI) youths, and there is scarce information on the risk and protective factors driving this behavior. Using the Arizona Youth Survey 2018, we analyzed data from 2494 students who self-identified as AI (aged 13–18 years, 47.31% male). Logistic regression models were used to examine the association between community attachment with lifetime and the past-30-days PDM. Community attachment was negatively associated with AI youths’ lifetime PDM (OR = 0.78, 95% CI [0.65, 0.92]); however, it was not significant for the past-30-days users (OR = 0.91, 95% CI [0.72, 1.15]). For both lifetime and past-30-days users, a common protective factor was close friends’ negative perceptions of PDM, while a common risk factor included siblings’ prescription drug use and ease of access to substances. Lifetime users’ drug-free closest friends were also protective. The findings support similar community-oriented approaches showing a cumulative rather than immediate effect, and past-30-days PMD youths were strongly influenced by peers and family. PDM risk and protective factors can advance knowledge about AI youths’ social and cultural determinants of health and influence future prevention interventions.

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