Ni/ZrO2-CeO2 catalysts with high loading of nickel have been prepared by the coprecipitation method and employed to investigate the catalytic hydrodeoxygenation (HDO) performance of guaiacol. The materials obtained were characterized using N-2 adsorption-desorption, X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, H-2-TPR, CO chemisorption, and NH3-TPD. For Ni/ZrO2-CeO2 catalysts, the formation of the ZrO2-CeO2 solid solutions enhances the dispersion of the metal Ni. The oxygen vacancies resulting from Ce3+ species in Ni/ZrO2-CeO2 promote the adsorption and activation of the oxygen-containing group in guaiacol molecules and thereby improve the ability of the catalyst to break the C-O bond. The addition of ZrO2 increases the number of acidic sites of the catalysts. These factors synergistically enhance the HDO performance of the catalysts.