Owing to their stability, SiO2 nanofluids have potential engineering applications for weakening the mechanical properties of coal and improving the water-injection effect in coal seams. The nanoparticle size is a pivotal factor that affects the properties of nanofluids. Herein, nanoindentation tests and scanning electron microscopy were utilized to probe the variations in the mesomechanical parameters of coal samples treated using nanofluids with various SiO2 particle sizes. It is demonstrated that the mechanical parameters of coal treated with disparately sized nanoparticles exhibit a drastic diminishment, followed by a rebound increase. The fundamental mechanical parameters of the coal samples treated with 30 nm nanoparticles present the most prominent change. Simultaneously, the degree of plastic damage of the coal after the nanoparticle modification treatment gradually enlarge, corresponding to a downward trend in the proportion of the elastic potential energy of the coal, which can remarkably lower the degree of energy release. Furthermore, large-size nanoparticles adsorbed on the surface of each group of coals readily agglomerate together due to their size to block the fractures. The SiO2 nanoparticles with a diameter of 30 nm can be noticeably adsorbed and aggregated inside the pore space of the coal, which could subsequently imbibe an overwhelming amount of water and notably loosen the adhesion among mineral particles, thereby lessening the binding force, and thus enforcing the degradation of mechanical properties. The research achievements are helpful in advancing the rational selection of nanoparticle parameters in nanofluid enhanced water injection.