Understanding how the shape of a nanocatalyst alters its catalytic performance is essential for the design of active catalysts at the nanoscale. This report describes novel findings of an investigation of CuO/CeO2 nano catalysts with different shapes for preferential CO oxidation (CO-PROX), aiming at unraveling the structural origin of the high catalytic activity. CuO/CeO2 catalysts with a series of shapes, including octahedron, rod, cube, sphere and spindle morphologies, were synthesized by a combination of hydrothermal and impregnation methods. By probing the structure, elementary valence and reductivity of the catalysts using an array of techniques, an intriguing structure-activity synergy is revealed, pinning the origin of the highest catalytic activity to the intersection of the nanocrystal planes. The CuO/CeO2 catalysts with spheres and spindles featuring exposed {111} and {002} crystal planes of CeO2 were found to exhibit the lowest reaction temperature in terms of 50% CO conversion and a wider temperature window for the complete CO conversion in CO-PROX. The catalytic synergy reflects a combination of high surface area, reduced state of copper sites, high oxygen vacancies, as well as stronger interaction between CuO and CeO2. This synergy was further substantiated by analysis of the results based on DFT calculation, showing that the oxygen vacancies were the highest at the intersection of {111} and {002} facets, but the lowest on CeO2 {111} surface. The finding of {111} and {002} facets with an increased oxygen vacancy and a stronger metal-support interaction for improving the catalytic performance has important implications for designing facet-tunable nanocatalysts for efficient PROX.