Because of energy crisis, how to minimize hydrogen consumption and improve the catalytic activity is of importance for the hydrodeoxygenation (HDO) of phenols. In this study, Co-Mo-S catalysts were prepared by a one-step hydrothermal method, and their properties were characterized by nitrogen physisorption, X-ray diffraction, and transmission electron microscopy. The effects of Co content and catalyst preparation temperature on the catalytic activity were studied using the HDO of p-cresol as a probe. The effects of reaction conditions such as temperature and hydrogen pressure on the conversion and product distribution were also studied. Adding Co into the MoS2 catalyst decreased its surface area but increased the HDO activity and reduced the hydrogen consumption. The HDO of p-cresol on Co-Mo-S proceeded with two separate reaction routes: hydrogenation-dehydration (HYD) and direct deoxygenation (DDO). The HDO active sites were well explained by the Rim-Edge model. The high conversion of p-cresol and low HYD/DDO was attributed to the short slab length and high number of layers in stacks, respectively.