The electrochemical CO reduction reaction (CORR) typically uses transition metals as the catalysts. To improve the efficiency, tremendous efforts have been dedicated to tuning the morphology, size, and structure of metal catalysts and employing electrolytes that enhance the adsorption of CO. We report here a strategy to enhance CORR by constructing the metal-oxide interface. We demonstrate that Au-CeO shows much higher activity and Faradaic efficiency than Au or CeO alone for CORR. In situ scanning tunneling microscopy and synchrotron-radiation photoemission spectroscopy show that the Au-CeO interface is dominant in enhancing CO adsorption and activation, which can be further promoted by the presence of hydroxyl groups. Density functional theory calculations indicate that the Au-CeO interface is the active site for CO activation and the reduction to CO, where the synergy between Au and CeO promotes the stability of key carboxyl intermediate (*COOH) and thus facilitates CORR. Similar interface-enhanced CORR is further observed on Ag-CeO, demonstrating the generality of the strategy for enhancing CORR.