Preferential oxidation of CO is beneficial to the removal of residual poisonous CO in reformate gas for proton exchange membrane fuel cell. Cu-CeO2 has been widely studied as a promising catalyst for this application. Herein, we have synthesized multi-shelled hollow Cu-CeO2 microspheres by a facile and one-step aerosol spray pyrolysis. Repeated and asynchronous combustion of carbon during the pyrolysis process results in the formation of multi-shelled hollow structure. Meanwhile, surface enrichment and high dispersion of copper species are achieved. This novel Cu-CeO2 catalyst exhibits full CO conversion in H-2-rich stream within a rather wide temperature window from 130 degrees C to 190 degrees C and a satisfying O-2 selectivity. In addition, it displays a decent catalytic stability, with a slight conversion decay of 3.3% and a high O-2 selectivity around 94% in continuous flow for 20 h. Based on the synergetic mechanism of copper-ceria catalysts, highly dispersed copper species and abundant CuOx/CeO2 interfaces in multi-shelled hollow microspheres give rise to the changes of redox properties and CO adsorption properties, and thus result in promoted catalytic performance.