Using data obtained from the Louisville Metro Emergency Medical Services, this article examined the spatial and temporal patterns of opioid overdoses in Louisville, Kentucky. We aggregated opioid overdoses to street segments and applied the optimized hot spot analysis to identify areas with significant high overdose rates. Multiple spatial regression models were used to explore the ecological risk factors potentially associated with the spatial variations of the epidemic. The results suggest an overall clustered pattern of opioid overdoses with all overdose incidents concentrated in less than 8% of all the street segments. The consecutive hot spots largely overlapped with the most disadvantaged inner-city neighborhoods in Louisville. Regression results provided statistical evidence regarding the effects of socioeconomic correlates including uninsured, vacancy rates, and criminal activity. The spatial discrepancy between the overdose hot spots and lack of medical facilities or hospitals in the disadvantaged neighborhoods points to the critical issue of health inequity.