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Vancouver’s Downtown Eastside (DTES), an urban indigenized space on unceded territory, is the site of a dense assemblage of public health interventions for addictions and epidemiological research on drug abuse prevention and treatment. In this community, and others across Canada, Indigenous peoples are differentially subject to the disciplinary modes of biomedical and state regulation through discourses of addiction. Addiction science has been used in the Canadian context to deflect from the historical legacies of colonialism and structural violence that shapes urban spaces like the DTES and the lives of urban Indigenous peoples. This ethnographic paper reflects on how medico-scientific knowledge of addiction and neurology are used to govern urban Indigenous communities, masking the racialization of addiction science in Canada. It asks: In which ways is contemporary addiction science a revised form of colonial logic at play (constructing settlers as compassionate saviours and Indigenous communities as dysfunctional and chaotic)? What would it mean to unsettle or decolonize addiction science in this space? If we acknowledge that the fields of STS and addiction science are both products of western thinking, white science, and if we consider the historical legacy of drugs and other substances in Canadian colonial law, how can we develop an approach that works to decentre western thinking on drug use in settler colonies? As a first step in unsettling addiction science and theory, this paper is anchored solely in Indigenous theory and narratives—scholarly, fictional, and non-fictional—as a means to displace settler epistemologies on addiction.