In this work, the structure−performance relationship of Cu/MgO catalysts was established to unravel the role of MgO and the active sites for CO hydrogenation to CH 3 OH synthesis, by intrinsic kinetics, chemical titration, and a series of in situ (operando) spectroscopic characterizations. The turnover rates of CH 3 OH formation on Cu/MgO catalysts, especially when the Mg/(Mg + Cu) atomic ratio is 0.67, were significantly higher than that on monometallic Cu particles. We have demonstrated that the rates were insensitive to the particle size of Cu but depended linearly on the quantity of Cu−MgO interfacial sites. The interaction between Cu and MgO particles improved the dispersion of Cu particles and formed more highly active Cu−MgO interfacial sites as identified by precise characterization. Moreover, this study has also unraveled that both the HCO* and HCOO* species are predominantly reactive intermediates, and their sequential hydrogenation occurs concurrently for CH 3 OH formation over Cu/MgO catalysts during the CO−H 2 reaction.