This work showcases an innovative route for biocompound upgrading via hydrodeoxygenation (HDO) reactions, eliminating the need for external high-pressure hydrogen supply. We propose the use of water as reaction media and the utilization of multifunctional catalysts that are able to conduct multiple steps such as water activation and HDO. In this study, we validate our hypothesis in a high-pressure batch reactor process using guaiacol as a model compound and multicomponent Ni-based catalysts. In particular, a comparison between ceria-supported and carbon/ceria-supported samples is established, the carbon-based materials being the suitable choice for this reaction. The physicochemical study by X-ray photoelectron spectroscopy, transmission electron microscopy, X-ray diffraction, and temperature-programmed reduction reveals the greater dispersion of Ni clusters and the strong metal-support interaction in the carbon/ceria-based samples accounting for the enhanced performance. In addition, the characterization of the spent samples points out the resistance of our catalysts toward sintering and coking. Overall, the novel catalytic approach proposed in this paper opens new research possibilities to achieve low-cost bio-oil upgrading processes.