The gas response characteristic toward C2H5OH has been demonstrated in terms of copper-vacancy concentration, hole density, and microstructural factors for undoped/Li(I)-doped CuO thin films prepared by sol-gel method. For the films, both concentrations of intrinsic copper vacancies and electronic holes decrease with increasing calcination temperature from 400 to 500 to 600 °C. Li(I) doping into CuO leads to the reduction of copper-vacancy concentration and the enhancement of hole density. The increase of calcination temperature or Li(I) doping concentration in the film increases both optical band gap energy and Cu2p binding energy, which are characterized by UV-vis-NIR and X-ray photoelectron spectroscopy, respectively. The overall hole density of the film is determined by the offset effect of intrinsic and extrinsic hole densities, which depend on the calcination temperature and the Li(I) doping amount, respectively. The apparent resistance of the film is determined by the concentration of the structural defects such as copper vacancies, Li(I) dopants, and grain boundaries, as well as by the hole density. As a result, it is found that the gas response value of the film sensor is directly proportional to the apparent sensor resistance.