Indigenous populations in Canada and globally experience a disproportionate burden of social and health-related risks and harms due to multigenerational impacts of colonialism, racialized policies, and related trauma. Associated outcomes include elevated rates of mental health and substance use disorders and devastating disconnection from traditions, culture, language, and spirituality. Despite decades of ongoing research and intervention efforts, conventional addiction treatment approaches continue to have only limited success among such vulnerable populations. This chapter elucidates the lived experiences of participants of a research project assessing the impact of ayahuasca-based therapy on addiction and other substance use-related outcomes among members of a rural Indigenous community in Western Canada. Quantitative findings demonstrated that ayahuasca therapy delivered in a ritualized retreat setting led to statistically significant reductions in problematic cocaine use, with some participants reporting complete cessation of drug use at follow-up. Increased connectedness with self, others, nature, and spirit was described as a key element associated with reduced cravings and substance use. This study highlights the therapeutic potential of ayahuasca-based therapy to facilitate deep and sustained healing and recovery from addiction for members of an Indigenous community, including some who had experienced highly traumatic histories and several failed treatment attempts. Given the heterogeneity of Indigenous populations, and distinct vulnerabilities associated with living in rural and remote settings, this study supports calls to advance research tailored to the needs of marginalized populations. Further research should explore how ayahuasca and other psychedelics affect connectedness and other factors that may improve well-being and facilitate recovery from addiction.