<p>The ethylene epoxidation process is crucial for selective chemical oxidation in various industrial applications. However, adding suitable promoters improves the selectivity of the commercially available Ag-catalyzed ethylene epoxidation toward ethylene oxide (EO). Empirical evidence suggests that cesium can significantly enhance the modest selectivity of silver; however, there is a need for more effective dual or multi-promoter combinations to achieve better selectivity for EO. In the present study, we employ a density functional theory (DFT) approach to investigate the impacts of Cs and various transition metal (TM) promoters—Re, Rh, Au, Cu, W, Zn, and Mo—on the ethylene epoxidation. We analyze the electronic properties of the catalysts, the adsorption energies of the reactants, and the activation barrier energies associated with the intermediates, utilizing fundamental principles and transition state theory. The results indicate that an optimal charge balance on the catalyst can be attained by combining electron-accepting TMs with electron-donating Cs. This balance effectively suppresses the formation of nucleophilic oxygen species that would otherwise improve ethylene combustion. It also mitigates the excessive electrophilicy of Ag centers, which facilitates EO isomerization. Therefore, the overall selectivity toward EO is enhanced. Indeed, the findings and methodologies presented in this work illustrate that the multi-promoted catalyst (Ag/Cs₂₂Cu₂₄Re₂₄Au₃₀) can substantially improve the selectivity of the EO reaction, with a shift in selectivity from 1.29 to 2.71 eV when compared to the pristine Ag (111) catalyst.</p>