Cigarette use remains the leading preventable cause of premature mortality in the US, with declines in smoking rates slowing in recent years. One promising target for improved tobacco control is the expanded regulation of tobacco retailers. Evaluations of such policy attempts have largely produced mixed results to date. The objective of this study was to the assess the potential of using a novel, residentially-focused zoning approach to produce a more targeted and equitable reduction in tobacco retailers in high-risk urban settings. We focused on Wilmington, Delaware, a city characterized by high poverty rates, a majority Black population, a disparate number of tobacco retailers, and an elevated smoking prevalence. Through the use of geospatial analyses, we observed disproportionately higher counts of convenience store tobacco retailers in medium- and high-density residential zones in Wilmington relative to the surrounding county. By linking electronic health record (EHR) data from a local health care system and US Census Bureau data, we further found that approximately 80% of Wilmington smokers and 60% of Wilmington youth lived in these residential zones. These findings highlight the potential to more equitably reduce tobacco retailer exposure through a residentially-focused zoning approach. Tobacco control policy and research implications are considered.