We report the comparative investigation on the electrochemical application of mesoporous copper oxide (Cu2O and CuO) microspheres with different surface areas as anode materials in Li-ion batteries. Mesoporous Cu2O microspheres with a narrow particle size distribution are synthesized by a hydrothermal method and CuO is obtained by subsequent oxidation of Cu2O. The synthesized mesoporous Cu2O and CuO microspheres possess a surface area of 12.7–65.8 and 5.2–37.6 m2 g−1 and an average crystal size of 15.0–20.5 and 10.4–15.9 nm, respectively. The result reveals that the mesoporous Cu2O and CuO microspheres with a higher surface area show a higher capacity and better cyclability than those with a lower surface area. The mesoporous Cu2O and CuO microspheres with a surface area of 65.8 and 37.6 m2 g−1 show an initial charge capacity of 430.5 mAh g−1 and 601.6 mAh g−1 and deliver a capacity as high as 355.2 mAh g−1 and 569.8 mAh g−1 at 0.1 C after 50 cycles, respectively. This is because the highly developed mesoporous structure can enhance the accommodation of lithium ions, shorten the diffusion distance for lithium ions, and increase the absorption of electrolyte.