Identifying the local environments of active sites of CuxCe1-xO2 solid solution for low-temperature CO oxidation remains significant challenges. In this study, we coupled density functional theory and microkinetic modeling to thoroughly investigate local structures of CuxCe1-xO2 solid solution catalysts, as well as its catalytic performance for low-temperature CO oxidation. Combined with the infrared spectra simulations, we propose that the substitution of Cu3 or Cu4 clusters for one Ce atom accounts for the experimentally observed vibrational peaks of the adsorbed CO, rather than the Cu single atom or dimer. Cu single-atom and Cun clusters (n = 2–4) doped into CeO2 all exhibit an excellent stability against ripening and a promising catalytic activity for low-temperature CO oxidation. This research for the first time elucidates the nature of CuxCe1-xO2 solid solution catalysts and paves the way for the rational design of Cu/CeO2 catalysts for CO oxidation.