Purpose Before the end of the 20th century, American Indians (AIs) primarily resided in nonmetropolitan areas. Shifting demographic trends have led to a majority of AIs now living in urban areas, leading to new health care barriers for AIs. AIs experience the poorest survival from all cancers combined compared to all other racial groups. Identifying and classifying barriers to cancer care may facilitate supportive interventions and programs to improve access and treatment. Methods A 5‐year cancer symptom management project targeted AIs in the Southwest. The first phase of the randomized clinical trial consisted of 13 focus groups (N = 126) of cancer patients/survivors and their caregivers. Discussions explored existing and perceived barriers and facilitators to cancer symptom management and cancer treatment. Findings Significant barriers to cancer‐related care were found among urban AIs, as compared to their rural counterparts. Barriers were classified within 4 subgroups: (1) structural, (2) physical, (3) supportive, or (4) cultural. Urban AIs reported barriers that are both structural and physical (inadequate access to care and public transportation) and supportive (lack of support, resources and technology, and less access to traditional healing). Rural participants reported communication and culture barriers (language differences, illness beliefs, and low levels of cancer care knowledge), as well as unique structural, physical, and supportive barriers. Conclusion It is important to identify and understand culturally and geographically influenced barriers to cancer treatment and symptom management. We provide recommendations for strategies to reduce health disparities for AIs that are appropriate to their region of residence and barrier type.