Based on the recently discovered peroxidase-like activity, cupric oxide nanoparticles with diameters about 6 nm were synthesized and used to remove phenol from aqueous solution. As a kind of peroxidase mimetic substance, cupric oxide nanoparticles can be used as a promising catalyst for the total oxidation of phenol in aqueous solutions by peroxidation, which therefore avoids the need of secondary-treatments. The mechanism study suggested that cupric oxide nanoparticles could catalyze hydrogen peroxide to form hydroxyl free radicals, which were mainly responsible for the removal of phenol. The catalytic conditions for the phenol degradation were extensively optimized among a range of pH as well as initial concentration of catalyst, H2O2 and phenol. High degradation efficiency of phenol can be achieved in relatively wide pH range from 3 to 7. Under optimized conditions, phenol (0.25 g/L) can be eliminated completely in 35 min. It can be potentially applied in treating the industrial wastewaters.