A group of CuO_x-CeO₂ catalysts for preferential oxidation of carbon monoxide (CO-PROX) is designed by constructing different distribution status of Cu species on similar CeO₂ support to adjust the Cu–Ce interaction strength. Cycled temperature programmed reduction by hydrogen (H₂-TPR) indicates the strength of Cu–Ce interaction can impact the amount and redox properties of surface highly dispersed CuO_x and strongly bonded Cu-[O_x]-Ce species, which respectively determines the catalytic performance at low and high temperature. Temperature programed desorption of H₂ (H₂-TPD) reveals the presence of large amounts of Cu-[O_x]-Ce species can inhibit H₂ adsorption and dissociation, which increases the O₂ selectivity toward CO oxidation. Moreover, temperature programmed desorption of CO₂ (CO₂-TPD) and in situ diffuse reflectance infrared Fourier transform spectra (DRIFTs) illustrates that H₂O and CO₂ influences the low-temperature catalytic performance mainly by competitive adsorption with CO on surface highly dispersed reactive Cu⁺ sites. This work aims to shed light on the underlying Cu–Ce interaction regime, and guide the design of high-performance CuO–CeO₂ catalysts in realistic reaction conditions.