Objectives: To investigate the association of state-level Medicaid expansion and non-elderly mortality rates from 1999 to 2018 in Northeastern urban settings.Methods: This quasi-experimental study utilized a synthetic control method to assess the association of Medicaid expansion on non-elderly urban mortality rates [1999–2018]. Counties encompassing the largest cities in the Northeastern Megalopolis (Washington D.C., Baltimore, Philadelphia, New York City, and Boston) were selected as treatment units (n = 5 cities, 3,543,302 individuals in 2018). Cities in states without Medicaid expansion were utilized as control units (n = 17 cities, 12,713,768 individuals in 2018).Results: Across all cities, there was a significant reduction in the neoplasm (Population-Adjusted Average Treatment Effect = −1.37 [95% CI −2.73, −0.42]) and all-cause (Population-Adjusted Average Treatment Effect = −2.57 [95%CI −8.46, −0.58]) mortality rate. Washington D.C. encountered the largest reductions in mortality (Average Treatment Effect on All-Cause Medical Mortality = −5.40 monthly deaths per 100,000 individuals [95% CI −12.50, −3.34], −18.84% [95% CI −43.64%, −11.67%] reduction, p = < 0.001; Average Treatment Effect on Neoplasm Mortality = −1.95 monthly deaths per 100,000 individuals [95% CI −3.04, −0.98], −21.88% [95% CI −34.10%, −10.99%] reduction, p = 0.002). Reductions in all-cause medical mortality and neoplasm mortality rates were similarly observed in other cities.Conclusion: Significant reductions in urban mortality rates were associated with Medicaid expansion. Our study suggests that Medicaid expansion saved lives in the observed urban settings.