The development of Pt-based bimetallic catalysts for ethanol oxidation reaction (EOR) is an important subject to enhance the performance of the promising and clean direct ethanol fuel cells (DEFCs). In this study, we thoroughly investigated EOR activity on Pt and its bimetallic catalysts PtM (M = Au, Ag and Sn) with different degrees of oxophilicity. The computational results found that EOR on Pt-based catalysts prefers the sequence of CH3CH2OH* → CH3CH2O* → CH3CHO* to form the main product of acetaldehyde and rate-determining step is controlled in the initial O–H bond cleavage. The foreign elements M can reduce the barrier to some extents. Additionally, their surface oxygen containing species (OCS) can further lower the barrier to better enhance EOR activity. Among those PtM, PtSn has the highest oxophilicity and the most abundant surface OCS, which can most effectively lower the barrier. Thus, the computational study predicted that PtSn shows the best EOR activity through bifunctional mechanism. Experimentally, PtM nanorods with varied surface OCS have been synthesized, characterized and applied for electrochemical tests. The enhanced EOR activity was observed on the PtM with significant amount of surface OCS. The computational and experimental efforts concluded that the oxophilicity plays an important role for the enhanced EOR activity, attributable to the highly active surface OCS.