Because of the abundance of natural gas in our planet, a major goal is to achieve a direct methane-to-methanol conversion at medium to low temperatures using mixtures of methane and oxygen. Here, we report an efficient catalyst, ZnO/Cu2O/Cu(111), for this process investigated using a combination of reactor testing, scanning tunneling microscopy, ambient-pressure X-ray photoemission spectroscopy, density functional calculations, and kinetic Monte Carlo simulations. The catalyst is capable of methane activation at room temperature and transforms mixtures of methane and oxygen to methanol at 450 K with a selectivity of ∼30%. This performance is not seen for other heterogeneous catalysts which usually require the addition of water to enable a significant conversion of methane to methanol. The unique coarse structure of the ZnO islands supported on a Cu2O/Cu(111) substrate provides a collection of multiple centers that display different catalytic activity during the reaction. ZnO-Cu2O step sites are active centers for methanol synthesis when exposed to CH4 and O2 due to an effective O-O bond dissociation, which enables a methane-to-methanol conversion with a reasonable selectivity. Upon addition of water, the defected O-rich ZnO sites, introduced by Zn vacancies, show superior behavior toward methane conversion and enhance the overall methanol selectivity to over 80%. Thus, in this case, the surface sites involved in a direct CH4 → CH3OH conversion are different from those engaged in methanol formation without water. The identification of the site-dependent behavior of ZnO/Cu2O/Cu(111) opens a design strategy for guiding efficient methane reformation with high methanol selectivity.