BackgroundNative American communities suffered disproportionately negative effects during the COVID-19 pandemic, yet no research has explored the experiences of rural Eastern Region Native Americans. MethodsInformed by the Native Reliance Model and Indigenous Standpoint Theory, we conducted a qualitative descriptive project in the Spring and Summer of 2022; data included semi-structured interviews and focus groups with 24 individuals representing five South Carolina tribal groups. FindingsThematic analysis yielded four emergent themes: 1) “Let's just finish the Indians off”: Pandemic distrust rooted in historical and contemporary Native American experiences; 2) “We have been misled”: Making sense of conflicting public health information; 3) “I'm not giving it to some innocent person”: COVID-19 mitigation behaviors as Native American cultural practice; and 4) “We put the plan in place”: Self-advocacy and action as a source of Native American pride and responsibility. InterpretationThese participants demonstrated resiliency grounded in family and tribal ties, even in the face of personal losses, economic struggles, and healthcare barriers. To strike a balance between cultural traditions and public health recommendations, public health practitioners should 1) build partnerships with community leaders, elders, and tribal health authorities to facilitate the development of culturally respectful interventions that address specific health concerns in the context of historical traumas; and 2) implement alternative methods of communication and engagement to ensure equitable access to healthcare services in rural locations, such as collaborating with community organizations, deploying mobile health units, and utilizing traditional channels of communication within these communities.