Various copper−ceria-based composites have attracted attention as efficient catalysts for the reduction of NO with CO. In this comparative study, we have examined the catalytic potential of different configurations of copper oxide−ceria catalysts, including catalysts based on a copper−ceria solid solution, copper oxide particles supported on ceria, and ball-milled copper oxide−ceria. The structurally different interfaces between the constituents of these catalysts afforded very different catalytic performances. The solid solution catalyst outperformed the corresponding ceria-supported and ball-milled CuO−CeO 2 catalysts. The copper cations incorporated into the ceria lattice strongly improved the activity, N 2 selectivity, and water vapor tolerance compared to the other catalyst configurations. The experimental observations are supported by first-principles density functional theory (DFT) studies of the reaction pathway, which indicate that the incorporation of Cu cations into the ceria matrix lowers the energy required for activating the lattice oxygen, thereby enhancing the formation and healing of oxygen vacancies, and thus promoting NO reduction with CO.