Mortality from opioid overdose has become the leading cause of non-natural death in Milwaukee County, Wisconsin in recent years. In order to better understand the opioid epidemic and formulate pro-active responses to the crisis at the local level, this study examines the spatial prevalence and associated factors of opioid overdoses that end in mortality in Milwaukee, WI using the spatial econometrics model. The social determinants of health framework is used to identify the potential related socioeconomic factors associated with opioid use and misuse. Using principal component analysis, 6 primary components are identified from the chosen social determinants and used as explanatory variables in the spatial econometric analysis. The age-adjusted standardized mortality rate is calculated for each census tract as the dependent variable in the analysis. Overall low socioeconomic status, labor-intensive occupations, income inequality, and the 20–34-year-old age group are identified as variables with a significant contribution to high overdose mortality rates, both directly and indirectly. A significant global spillover effect is also identified at the census tract level, indicating the severity of the opioid epidemic in Milwaukee County. This study reveals the overall contribution that socioeconomic factors have on the opioid epidemic and their associated feedback effects, providing targeted information on the opioid epidemic.