Pt-oxygen-containing species (Pt-OCS) catalysts, in which OCS (e.g., metal-oxides) are decorated on a Pt surface, possess enhanced ethanol oxidation reaction (EOR) activity and stability compared with pure Pt and are promising in practical applications of direct ethanol fuel cells. We investigate the promotion roles of Pt-OCS electrocatalysts toward the EOR via a combination of density functional theory (DFT) calculations and experiments, providing a rational design strategy for Pt-OCS catalysts. It is revealed that Pt-AuO and Pt-SnO excel in EOR activity and stability, respectively, among the DFT screening of various Pt-OCS systems, and this is confirmed by the following experiments. Moreover, an optimized Pt-AuSnO catalyst is proposed by DFT calculations, taking advantage of both Pt-AuO and Pt-SnO. The as-prepared Pt-AuSnO catalyst delivers an EOR activity that is 9.7 times higher than that of Pt and shows desired stability. These findings are expected to elucidate the mechanistic insights into Pt-OCS materials and lead to advanced EOR electrocatalysts.