Cu-doped manganese oxide (Cu–Mn2O4) prepared using aerosol decomposition was used as a CO oxidation catalyst. Cu was successfully doped into Mn2O4 due to their nitrate precursors having closed thermal decomposition properties, which ensured the atomic ratio of Cu/(Cu + Mn) in Cu–Mn2O4 close to that in their nitrate precursors. The 0.5Cu–Mn2O4 catalyst of 0.48 Cu/(Cu + Mn) atomic ratio had the best CO oxidation performance, with T50 and T90 as low as 48 and 69 °C, respectively. The 0.5Cu–Mn2O4 catalyst also had (1) a hollow sphere morphology, where the sphere wall was composed of a large number of nanospheres (about 10 nm), (2) the largest specific surface area and defects on the interfacing of the nanospheres, and (3) the highest Mn3+, Cu+, and Oads ratios, which facilitated oxygen vacancy formation, CO adsorption, and CO oxidation, respectively, yielding a synergetic effect on CO oxidation. DRIFTS-MS analysis results showed that terminal-type oxygen (M=O) and bridge-type oxygen (M-O-M) on 0.5Cu–Mn2O4 were reactive at a low temperature, resulting in-good low-temperature CO oxidation performance. Water could adsorb on 0.5Cu–Mn2O4 and inhibited M=O and M-O-M reaction with CO. Water could not inhibit O2 decomposition to M=O and M-O-M. The 0.5Cu–Mn2O4 catalyst had excellent water resistance at 150 °C, at which the influence of water (up to 5%) on CO oxidation could be completely eliminated.