Identifying the active sites and reaction kinetics for a catalytic reaction can provide significant insight into the catalytic systems. By use of DFT calculations, the catalytic activity of FeO/Pt(111) interfacial sites, which is an important class of catalyst with excellent activity, for methanol partial oxidation is carefully examined and compared. The O–H cleavage barrier of methanol is significantly diminished to below 0.1 eV with the aid of interfacial oxygen, which is much lower than that on the Pt(111) surface (>0.8 eV). The CH3O* intermediate can further undergo a C–H bond breaking process to produce formaldehyde via a low barrier (∼0.2 eV) at the interfacial Pt sites. Assisted by an interfacial Pt–O ensemble, the O–H and C–H bond cleavages are greatly facilitated, suggesting that the FeO/Pt biphasic system could effectively combine the advantages of two individual phases. To investigate the rate-determining steps, a multisite microkinetic model is applied at the FeO/Pt interface. The results show that the overall rate can be significantly improved by lowering the activation energy of interfacial oxygen removal steps. Interestingly, the turnover frequency (TOF) can also be increased when the barriers of O2 dissociative adsorption on the Pt flat surface are increased, which is a special feature in multiphasic systems in comparison with the monophasic system. The active site and microkinetic studies in our work can provide insights into the development of metal/oxide catalysts for the partial oxidation of methanol or other primary alcohols.