Culturally relevant stressors and protective factors are vital to understanding and effectively supporting Native American/Alaska Native (NA/AN) college students' mental health and well-being. This study examined the theorized pathways among historical loss, well-being, psychological distress, and the proposed cultural buffer of ethnic identity in the indigenist stress-coping model (ISCM). Cross-sectional data were collected via online survey and analyzed using structural equation modeling. Participants were a national sample of 242 NA/AN college students. Participants were predominantly women (n = 185; 76%) and median age was 21 years. Partial support was found for the ISCM. Participants reported frequent thoughts of historical loss, which were associated with lower well-being and higher levels of psychological distress. Ethnic identity moderated the relationship between historical loss and well-being such that those with stronger ethnic identities reported a weaker relationship between historical loss and lower well-being. Results underscore the importance of culturally specific risk and protective factors in NA/AN college students' resiliency and inform needed interventions and systemic change in higher education. (PsycInfo Database Record (c) 2023 APA, all rights reserved).