The COVID-19 pandemic compounds stressors of daily life among American Indian/Alaska Natives. This study investigated the impact of COVID-19 among American Indian/Alaska Natives and non-Hispanic whites by examining depressive symptoms, overall stress, resilience, and coping, utilizing the Transactional Model of Stress and Coping. Of the 207 individuals participating in this study, 109 identified as American Indian/Alaska Native and 98 as non-Hispanic white. Despite demographic similarities, American Indian/Alaska Natives exhibited more stressors related to COVID-19 as well as higher depressive symptom scores compared to non-Hispanic whites. Furthermore, COVID-19 stressors were more positively correlated with depressive symptoms for American Indian/Alaska Natives than non-Hispanic whites. For American Indian/Alaska Natives, the predominant coping processes identified were planful problem solving, escape-avoidance, and self-controlling. This study provides data to support programs and policies centered on improving the psychosocial health for American Indians/Alaska Natives and decreasing COVID-19-related health disparities.