Display omitted ► Efficient CuO/MnO2 catalysts have been developed for CO oxidation. ► CuO/MnO2 catalysts with CuO loading of 1–40% exhibit almost the same catalytic performance toward CO oxidation. ► The CuO–MnO2 interface is the active site for CO oxidation in CuO/MnO2 catalysts. ► CO oxidation over CuO/MnO2 catalysts likely follows the interfacial reaction mechanism. A series of CuO/MnO2 catalysts with different CuO loadings were synthesized by the incipient wetness impregnation method. The catalysts were characterized by N2 adsorption–desorption isotherms, powder X-ray diffraction, X-ray photoelectron spectroscopy, H2-temperature programmed reduction, CO-temperature programmed reduction and scanning electron microscope. The CuO/MnO2 catalysts with CuO loading of 1–40% exhibit almost the same catalytic performance toward CO oxidation while those with higher CuO loadings exhibit a much poorer catalytic activity. The structural characterization results demonstrate that the CuO–MnO2 interface is the active site for CO oxidation in CuO/MnO2 catalysts and CO oxidation over CuO/MnO2 probably follows the interfacial reaction mechanism in which CO chemisorbed on CuO reacts with oxygen species on MnO2 at the CuO–MnO2 interface.