Co-promotion of Ag catalysts by Re and Cs leads to ethylene oxide (EO) selectivity higher than that achievable by either promoter alone. However, the atomistic and electronic mechanisms behind this synergistic co-promotion remain unclear. Here, we shed light on how Re and Cs promote ethylene epoxidation by elucidating realistic catalyst models using machine learning-accelerated first-principles simulations, characterizing their electronic properties, and constructing structure–selectivity relationships. Together with a comprehensive set of experimental data, we show that the synergistic effects of co-promotion are twofold. First, Re, in the form of ReO 4 , increases the dispersion of Cs, thereby maximizing the promotional effects of Cs. Second, combining electron-withdrawing Re and electron-donating Cs balances the amount of charge transferred to the catalyst. Akin to the Sabatier principle, this maximizes EO selectivity by preventing the formation of overly nucleophilic oxygen species that facilitate ethylene combustion and overly electrophilic Ag centers that accelerate EO isomerization. The insights from our work may guide the development of improved promoter combinations, while our methodology may serve as a template for studying other complex, multiply promoted reaction systems.