Indigenous Peoples who use illicit drugs (IPWUID) are disproportionately represented among toxic drug poisoning deaths in Canada. These drug-related harms are framed by the historical and ongoing trauma related to settler colonialism and are acutely visible in Vancouver, Canada's Downtown Eastside - a low-income neighbourhood that is an epicenter of the drug poisoning crisis and characterized by entrenched poverty, substance use, violence, and homelessness. This study was undertaken to examine the experiences and perspectives of IPWUID in the Downtown Eastside regarding the drug poisoning crisis and the responsiveness of harm reduction programs within the context of settler colonialism. Indigenous-led qualitative interviews were conducted with 16 IPWUID recruited by Indigenous peer researchers. Indigenous ways of knowing were embedded throughout the entire research design to ensure research was culturally congruent. Interview transcripts were analyzed thematically and interpreted by drawing on concepts of social violence and racial capitalism. Our analysis reviewed three key themes that centered the experiences of IPWUID in Vancouver's Downtown Eastside in relation to the drug poisoning crisis: (1) that the drug poisoning crisis is understood as a form of genocide toward Indigenous Peoples; (2) that the crisis is experienced within the context of pervasive distrust and adversarial relationships with police rooted in structurally racist experiences of place-based policing practices; and (3) that there is a desire for culturally-safe harm reduction care with Indigenous representation, cultural integration, and that addresses inequities and injustice stemming from colonialism and structural racism. Findings demonstrate how responses to the drug poisoning crisis among IPWUID need to respond to social and materials conditions perpetuated by colonialism and racial capitalism, while also centering IPWUID through the development and implementation of Indigenous-led and culturally safe harm reduction approaches.