The high-efficiency conversion of biomass resources to biofuels has attracted widespread attention, and the active sites and synergistic effect of catalysts significantly impact their surface arrangement and electronic structure. Here, a nickel-based transition metal carbide catalyst (Ni/TMC) with high Lewis acidity was prepared by self-assembly of transition metal carbide (TMC) and nickel, which exhibited excellent performance on synergistic hydrogenation and hydrogenolysis of 5-hydroxymethylfurfural (HMF) into liquid biofuel 2,5-dimethylfuran (DMF). Notably, Ni/WC with the highest Lewis acidity (4728.3 μmol/g) can achieve 100% conversion of HMF to 97.6% yield of DMF, with a turn-over frequency of up to 46.5 h−1. The characterization results demonstrate that the rich Lewis acid sites yielded by the synergistic effect between Ni species and TMC are beneficial for the CO hydrogenation and C–O cleavage, thereby accelerating the process of hydrodeoxygenation (HDO). Besides, a kinetic model for the HDO of HMF to DMF process has been established based on the experimental results, which elucidated a significant correlation between the measured and the predicted data (R2 > 0.97). Corresponding to the adsorption configuration of Ni/WC and substrate determined by in-situ FTIR characterization, this study provides a novel insight into the selective conversion of HMF process for functional biofuel and bio-chemicals.