<p>Northern Ontario is the largest and least populated region of the Canadian province of Ontario. Like other rural, remote, and northern regions, Northern Ontario has been disproportionately impacted by the opioid crisis, with an opioid-related mortality rate more than twice that of the province as a whole. Social exclusion is a predictor of drug use, and the urban core–hinterland periphery socioeconomic relationship that undergirds Northern Ontario’s economy results in social degradation and economic marginalization. Along with deindustrialization and increased employment precarity, lack of access to health services, and higher rates of work-related pain, the exclusion inherent to the core–hinterland relationship increases risk of opioid-related mortality. Although the inequities in both the determinants and outcomes of substance use in Northern Ontario are stark, research, policy, and intervention continue to focus on Southern Ontario.</p>