The adsorption and dehydrogenation of ethanol over bimetallic clusters Pt6M (M = Co, Ni, Cu, Zn, Ru, Rh, Pd, Sn, Re, Ir, and Pt) have been investigated with the density functional theory. The fully optimized Pt6M are used to model the catalyst surfaces of bimetallic nanoparticles. The reaction potential energy profile contains two adsorption modes and three dehydrogenation paths. For all Pt6M, the CH3CH2O*H adsorption is more favorable than CH3CH*2OH*. The hydroxyl dissociation is more advantageous than α-hydrogen dissociation from both kinetics and thermodynamics. Compared with Pt alone, Re and Ru are predicted to involve positive alloy effect enhancing the adsorption of ethanol and lowering the dehydrogenation barrier. However, Sn and Zn are not suitable for ethanol electro-oxidation. The conclusion is also confirmed by charge transfer and electron density on frontier molecular orbitals. Media effects are simulated via addition of one H2O and OH− in different adsorption modes with medium assistance.