Cu clusters supported on CeO 2 have been reported as a promising and active catalyst for CO oxidation. However, the identification of interfacial interactions and active sites is still a great challenge. In this work, we demonstrated that interfacial chemistry can be understood and predicted by using a simple descriptor of adsorbate-surface interactions that uncovers structure-activity relationships. The catalytic activity of CeO 2 supported Cu clusters for CO oxidation was studied by density functional theory. The CuÀ Ce dual site mechanism enables the Cu/CeO 2 catalyst to have a much lower reaction energy barrier than the Mars-van Krevelen (M-vK) mechanism and the Cu-only mechanism. The reaction energy barriers of Cu/CeO 2-x with an oxygen vacancy on the CeO 2 surface were 0.10, 0.37 and 0.77 eV, respectively. The excellent performance of Cu/CeO 2 catalysts is related to the interfacial interaction between Cu and CeO 2 and their synergistic redox behaviors, and oxygen vacancies facilitate the generation and stabilization of active Cu + species through the interaction with Cu clusters. And we have identified the binding energy of O 2 * can describe the CO oxidation activity of Cu/CeO 2 . Our study provides insight into the nature of active sites for Cu/CeO 2 catalysts and guidance for high-performance.