(1) Background: Silica nanoparticles (SiO NPs) have a high potential for human exposure and tend to accumulate in the liver. This study aimed to explore the size-dependent cytotoxicity induced by SiO NPs and identify key molecular pathways at the in vitro level through proteomics, metabolomics, and a combination of multiple omics methods. (2) Methods: The human hepatoma cells (HepG2) cells were exposed to SiO NPs of three different sizes (60, 250, and 400 nm) at doses of 0, 12.5, 25, 50, 100, and 200 μg/mL for 24 h. (3) Results: Exposure to 60 nm SiO NPs induced more reduction in cell viability than the other two larger-scale particles. Changes in the metabolomic and proteomic profiles of HepG2 cells induced by SiO NPs were also size-dependent. The main pathways that were significantly affected in the 60 nm SiO NPs treatment group represented cholesterol metabolism in proteomics and central carbon metabolism in metabolomics. Moreover, common enrichment pathways between differential proteins and metabolites included protein digestion and absorption and vitamin digestion and absorption. (4) Conclusions: Exposure to SiO NPs could induce size-dependent cytotoxicity and changes in proteomics and metabolomics, probably mainly by interfering with energy metabolism pathways.