Background: In Canada, the rate of opioid use, opioid use disorder (OUD), and associated mortality and morbidity are higher among Indigenous Peoples than the general population. Indigenous Peoples on medications for opioid use disorders (MOUD) often face distinct barriers that hinder their clinical progress, leading to treatment attrition. Methods: We used a social-ecological model to inquire into clients’ experiences with a history of treatment failure for OUD. We used exploratory qualitative research to engage 22 clients with a history of OUD treatment dropouts and who are currently on MOUD. In-depth, semi-structured interviews lasting an average of 30 minutes were conducted on-site. Results: We identified 4 themes from the study: (a) risk for substance use; (b) factors sustaining substance use; (c) factors leading to treatment, and (d) treatment failure and re-enrollment. Conclusion: Using a socio-ecological model helps to understand factors that influence an individual’s risk for OUD, decision to pursue treatment, and treatment outcomes. Furthermore, social ecological model also creates possibilities to develop supportive, multilevel interventions to prevent OUD risks and support for clients on MOUD. Such interventions include mitigating adverse childhood experiences, supporting families, and creating safe community environments.