It is challenging to improve the low-temperature activity of Ni-based catalyst for the CO2 methanation reaction. In this study, a molybdenum-doped cerium oxide supported Ni catalyst (Ni/MoCe) was constructed, and it showed remarkable CO2 methanation performance at low temperatures (<300 °C). Structural analysis revealed that the incorporation of Mo into the CeO2 lattice could enrich the surface oxygen vacancies, reduce the particle size of Ni species and enhance the metal-support interaction. The Ni/MoCe demonstrated a faster HCOO* pathway for the conversion of CO2 to CH4 compared with Ni/CeO2. Besides, the rich surface oxygen vacancies in Ni/MoCe facilitated the adsorption form of bidentate carbonates and the enhanced Ni-CeO2 interaction reduced the approach resistance of active H species from Ni for subsequent hydrogenation process. This work proves that Mo doping is an effective vacancy engineering strategy to design high-performance heterogeneous catalysts for CO2 hydrogenation.