Healthcare disparities in the initial management of patients with acute coronary syndrome (ACS) exist. Yet, the complexity of interactions between demographic, social, economic, and geospatial determinants of health hinders incorporating such predictors in existing risk stratification models. We sought to explore a machine-learning-based approach to study the complex interactions between the geospatial and social determinants of health to explain disparities in ACS likelihood in an urban community. This study identified consecutive patients transported by Pittsburgh emergency medical service for a chief complaint of chest pain or ACS-equivalent symptoms. We extracted demographics, clinical data, and location coordinates from electronic health records. Median income was based on US census data by zip code. A random forest (RF) classifier and a regularized logistic regression model were used to identify the most important predictors of ACS likelihood. Our final sample included 2400 patients (age 59 ± 17 years, 47% Females, 41% Blacks, 15.8% adjudicated ACS). In our RF model (area under the receiver operating characteristic curve of 0.71 ± 0.03) age, prior revascularization, income, distance from hospital, and residential neighborhood were the most important predictors of ACS likelihood. In regularized regression (akaike information criterion = 1843, bayesian information criterion = 1912, χ2 = 193, df = 10, p < 0.001), residential neighborhood remained a significant and independent predictor of ACS likelihood. Findings from our study suggest that residential neighborhood constitutes an upstream factor to explain the observed healthcare disparity in ACS risk prediction, independent from known demographic, social, and economic determinants of health, which can inform future work on ACS prevention, in-hospital care, and patient discharge.