Supported CuO-CeO2 catalysts have been extensively studied for their outstanding catalytic activity in CO oxidation. Unfortunately, they are prone to sintering and deactivation when exposed to high-temperature automotive exhausts. Herein, taking advantage of the heat-resistant SiO2 microspheres, we fabricated a series of core-shell-structured yCuO- xCeO2@SiO2 ( x is the weight ratio of CeO2-SiO2 and y is the weight ratio of Cu-(CeO2@SiO2)) composite catalysts. All the small CeO2 particles were bound to the SiO2 spheres, forming an xCeO2@SiO2 structure, on the surface of which a certain amount of CuO was well-dispersed. The 5CuO-50CeO2@SiO2 catalyst exhibited good activity, with the full conversion of CO achieved at around 130 °C, and no obvious deactivation was observed in the stability test. Importantly, the interaction between CuO and CeO2@SiO2 enhanced its durability at high temperatures. Even at 800 °C and with a space velocity of 800 000 mL·gcat-1·h-1, CO conversion could be maintained at 90%, which is prospectively applied in a real CO elimination system. The result of the temperature-programmed reduction in hydrogen demonstrated that this special core-shell-structured 5CuO-50CeO2@SiO2 catalyst improved the reduction ability of the CuO species. In situ diffuse reflectance infrared Fourier transform spectroscopy measurements further confirmed that CO molecules preferred to be adsorbed on Cu(I) species to form reactive CO-Cu(I) that enhanced the reactivity of the 5CuO-50CeO2@SiO2 catalyst.