Clinical reports on hepatotoxicity that arise from Rhizoma Paridis have recently received widespread attention. Because the hepatotoxicity mechanism is little understood, this research strived to investigate the hepatotoxicity mechanism of Rhizoma Paridis extracts based on iTRAQ quantitative proteomics and metabonomics. The extraction solutions were administrated to rats for 7 days by gavage, and the hepatotoxicity was assessed through quantification of biochemical indexes and Oil red O staining. Additionally, the mechanism of hepatotoxicity was investigated by metabonomics based upon GC-MS and iTRAQ quantitative proteomics. The biochemical and histopathological analysis stood out that Rhizoma Paridis extract could induce liver injury, which was proved by the formation of fat droplets, the changes of mitochondrial structure, and biochemical parameters. The iTRAQ proteomics and metabonomics revealed that Rhizoma Paridis-induced hepatotoxicity was chiefly connected with the abnormal activity of mitochondrion function, which brought about oxidative stress injuries and inflammation, finally causing cell apoptosis. Collectively, we have provided previously uncharacterized hepatotoxic mechanism induced by Rhizoma Paridis and a reference to ensure its safe use in the future.