BACKGROUND: American Indian and Alaska Native (AI/AN) communities' resiliency perseveres despite the disproportionate impact of the opioid crisis. Medication-assisted treatment (MAT) combines traditional psychosocial therapy with pharmacotherapies and has emerged as the standard of care for individuals with alcohol and opioid misuse. Combining traditional healing, evidence-based practices, and medications for the treatment of substance misuse to create a form of MAT that is culturally appropriate for AI/AN communities has proven challenging. This study explores how AI/AN culture and community perceptions impact the acceptability and feasibly of MAT and insights into what intervention components would support its provision. METHODS: Two health and human service care systems serving primarily AI/AN populations participated in the study. An Advisory Board consisting of clinical providers, program administrators, evaluation specialists, tribal members, and researchers led this project following community-based participatory research principles. Qualitative data was obtained over two waves of data collection, the first wave focusing on describing the cultural, community, systems, and clinical contexts for MAT implementation. The second wave gathered feedback on the feasibility and acceptability of intervention components developed from findings from the first wave. Participants in focus groups and key informant interviews (N = 41 with 29 participating in both waves of data collection) were at least 18 years of age and involved in substance misuse treatment services. Analysis involved extracting themes following principles of grounded theory to identify perspectives within and across each participating community. RESULTS: In the first wave of data collection, major themes included regulatory issues, procedural issues, clinical issues and the availability of consultation to therapists and counselors regarding MAT. In the second wave of data collection, participants reported that tribal, state, and federal resources for prescribing providers in response to the opioid crisis were robust and the gap was in supporting patients, their families, and therapists. CONCLUSIONS: These results supported the Advisory Board in identifying the following intervention components to improve access to MAT: 1) the provision of patient and family educational materials and 2) education and clinical consultation opportunities for therapists and counselors to support them in discussing MAT as a treatment option for their patients.