Modern industry has an increasingly urgent demand for high-performance greases, especially under extreme working conditions, where the insufficient performance of traditional greases has become increasingly prominent. This study used ultrasonication to mix MoS2 and mesoporous silica nanoparticles (MSNs) to prepare MoS2-MSNs, aiming to investigate the synergistic effect of the two components on the physicochemical properties and tribological performance of calcium sulfonate complex grease (CSCG). The results indicated that the incorporation of MoS2-MSNs improved water washout resistance and evaporation resistance of the CSCG by 38.15 and 35.29%. When the concentration of MoS2-MSNs was 1.0 wt.%, the maximum non-seizure load of the grease was increased by 33.96% compared with the base grease, and the coefficient of friction was reduced by 34.65%. Mechanism analysis revealed that MoS2-MSNs enhance the performance of CSCG through the advantages of multiple structures: MSNs adsorb and release base oil via their pore structure to achieve continuous lubrication and can inhibit the agglomeration behavior of MoS2, thereby optimizing the lubrication state.