The interaction and reaction of MeOH with Cu is of foremost importance in a range of heterogeneously catalyzed processes. A critical intermediate in the molecular transformation of MeOH on Cu-based catalysts is the methoxy species, the formation of which comprises the first elementary step in the MeOH steam reforming reaction. The interface length between metallic Cu(1 1 1) and copper oxide dictates the conversion of MeOH to formaldehyde (H2CO), although the microscopic details of MeOH’s adsorption, diffusion, and reaction at this complex interface are not clear. Here, STM was used to study the reaction of MeOH with the morphologically complex Cu(1 1 1)/copper oxide [Cu(1 1 1)/CuOx] surface. STM is the only technique that can simultaneously characterize various complex oxide surface structures and MeOH’s adsorption and reaction sites at the atomic scale. Variable-temperature STM measurements enabled the spatial distribution of both intact and dissociated MeOH to be tracked as the reaction proceeded and revealed that diffusion and spillover are key processes in MeOH decomposition. The presence of extended metallic Cu areas interconnected with disordered oxide structures, coupled with the weak binding of MeOH on Cu, provides the driving force for MeOH to migrate to interfacial sites at which deprotonation occurs. At elevated temperatures, methoxy buildup at the Cu(1 1 1)/CuOx interface is observed along with evidence consistent with spillover. These data provide the first clear atomic scale picture of the interaction and reaction of MeOH with oxidized Cu(1 1 1), the most common facet of Cu in nanoparticle catalysts.