The use of a computation-guided method and the discovered structure-property relationship would establish a rational strategy to aid the development of ethanol oxidation reaction (EOR) catalysts for possible commercialization of direct ethanol fuel cells. Here, we investigate the promotion roles of additive metals in ternary Pt-Sn-Ag catalysts toward EOR via a combination of density functional theory calculation and experimental evidence. By calculating the EOR energetics, the promotion roles of Sn and Ag were revealed from the viewpoints of electronic and structural effects, respectively: (1) The addition of Sn and Ag on Pt essentially reduce the reaction energy and activation barrier of the second two-electron transfer process of EOR, facilitating the oxidation of acetaldehyde to acetic acid; (2) a homogeneous Pt-Sn-Ag surface configuration strengthens the adsorption energy of ethanol, thus improving the activity for ethanol oxidizing to acetaldehyde. Experimentally, various Pt-Sn-Ag nanorod catalysts with different surface configurations were synthesized, and their electrochemical performances demonstrate the two EOR promotion effects as predicted. Notably, our extended Pt6-Sn-Ag nanorod catalyst shows remarkably enhanced EOR activity and stability, highlighting a homogeneous Pt-Sn-Ag surface configuration as an optimal structure for EOR catalysts.