Growing cupric oxide (CuO) nanowires (NWs) through thermal oxidation of copper (Cu) in air is a facile and low-cost strategy. In a temperature range of 673–1073 K, single-crystal, bi-crystal NWs and cone-shaped nanostructure usually coexist. As far as the underlying mechanism is concerned, the stress-driven grain-boundary (GB) diffusion mechanism has been the most successful theory up to now. However, it did not include the influence of oxygen partial pressure and cannot explain the growth of long single-crystal CuO NWs of uniform diameters. Thus, the CuO NWs growth mechanism is yet to be fully understood. In this study, we present that synergistic effects of the Kirkendall effect, stress-driven GB diffusion, large surface free energy gap between Cu2O and CuO facets and an effective electric field along the CuO NWs originating from oxygen gradient are mainly involved in the thermal growth of CuO NWs.