For CO catalytic oxidation, Cu and Ce species are of great importance, between which the synergistic effect is worth investigating. In this work, CeO2/Cu2O with Cu2O {111} and {100} planes were comparatively explored on CO catalytic oxidation to reveal the effects of interfacial electronic interactions and oxygen defects. The activity result demonstrates that CeO2/o-Cu2O {111} has superior performance compared with CeO2/c-Cu2O {100}. Credit to the coordination unsaturated copper atoms (CuCUS) on o-Cu2O {111} surface, the interfacial electronic interactions on CeO2/o-Cu2O {111} are more obvious than those on CeO2/c-Cu2O {100}, leading to richer oxygen defect generation, better redox and activation abilities of CO and O2 reactants. Furthermore, the reaction mechanism of CeO2/o-Cu2O {111} on CO oxidation is revealed, i.e., CO and O2 are adsorbed on the CuCUS on Cu2O {111} and oxygen defect of CeO2, respectively, and then synergistically promote the CO oxidation to CO2. The work sheds light on the designing optimized ceria and copper-based catalysts and the mechanism of CO oxidation.