Co-promoted MoS2 catalysts as good candidates can effectively remove the oxygen in bio-oil through the hydrodeoxygenation (HDO) of phenolics. However, it is of great importance to maximize the synergistic effect between Co and MoS2 which is conductive to the design of highly efficient Co-doped MoS2 HDO catalysts. Herein, two model catalysts with Co-Mo-S and CoS2/MoS2 (remote control model) as the active phases were successfully constructed and evaluated in the HDO of p-cresol. It was found that Co-Mo-S catalyst showed a significantly higher intrinsic HDO activity than CoS2/MoS2 catalyst, and the synergy factor between Co dopant and MoS2 of Co-Mo-S was 3.1 times that of CoS2/MoS2. The greatly enhanced HDO performance of Co-Mo-S catalyst is attributed to remarkably weakened strength of MoS bond, which can facilitate the sulfur vacancies (Vs) formation on the sulfur edges and promote the reaction rate of direct deoxygenation (DDO) pathway. This work revealed that Co-Mo-S model could better promote the CoMo synergy than the remote control model so as to design more efficient MoS2-based catalysts for HDO reactions.