A combination of in-situ diffuse reflectance infrared spectroscopy (DRIFTS) analysis and first-principles density-functional-theory (DFT) based calculations were used to uncover the fundamental phenomena associated with ethanol oxidation on platinum group metal (Pt, Rh, and Pd) containing catalysts. We show that metal particles accumulate oxygen at their surface and play the key role in burning ethanol molecules and their fragments. The oxide substrates at which the mobility of molecular fragments is high provide the highest supply rate of these species to the metal particles (and the highest oxidation rate). We investigated other factors that affect the ethanol oxidation including the shape of metal nanoparticles, the reactivity of the perimeter sites between the particle and the substrate, and the ability of oxygen atoms and molecular fragments to move from the nanoparticle to the substrate. These results explain the differences in ethanol oxidation process for different metals/oxide substrate catalysts.