ABSTRACT Purpose The top causes of death for American Indians (AIs), including heart and liver disease, are associated with alcohol use. Using the culturally based Framework of Historical Oppression, Resilience, and Transcendence (FHORT), the purpose of this article was to examine AI alcohol use from a sex-specific wellness approach, exploring its associated physical, behavioral, and mental risk and protective factors. Method Data were drawn from a cross-sectional survey with 479 AI adults in South Dakota. We employed a series of multiple hierarchical regression analyses to assess the associations of demographic (sex, age, marital status, income, and educational attainment), physical (Body Mass Index and cardiovascular risk), behavioral (smoking and health self-efficacy) and mental (depressive symptoms) factors with alcohol use. Results Results indicated that surveyed males tended to drink three times that of females, and depressive symptoms were associated with higher levels of alcohol use. Discussion This study highlights the need to examine AI alcohol use with sex in mind.