Catalytic hydrodeoxygenation (HDO) is a promising technology for improving the properties of pyrolysis bio-oils. However, the role that intermolecular reactivity between the numerous chemical components of bio-oil plays on the overall performance of the process has been scarcely investigated. In order to gain additional insights into the network of chemical processes taking place during bio-oil upgrading, the present work investigates the hydrodeoxygenation of mixtures of guaiacol and propionic acid using Ni based catalysts supported on solids exhibiting different acidity and textural characteristics: hierarchical ZSM-5 (h-ZSM-5), SBA-15 and Al-SBA-15. In addition, to the products of the HDO of each component of the binary mixture, such cyclohexane and propane, this work shows that hydrodeoxygenation is coupled with esterification, which occurs as a consequence of the in situ formation of methanol by demethoxylation of guaiacol, and other alcohols produced by hydrogenation. Minor contributions of alkylation reactions to the final product distribution are also revealed. Those secondary processes increase the chain length of the products and they contribute positively to avoid carbon losses in the gas phase. Results reported here indicate that the use of acidic supports improves the catalytic behavior leading much higher HDO degree. In this sense, Ni/h-ZSM-5 catalyst shows HDO values close to 100% and significant esterification activity, becoming a very promising catalyst for improving bio-oils properties as advanced biofuel.