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Non-alcoholic fatty liver disease (NAFLD) includes conditions such as steatosis, non-alcoholic steatohepatitis, and ultimately hepatocellular carcinoma. Although the pathology of NAFLD is well-established, NAFLD-induced drug metabolism mediated by cytochrome P450 (CYP) in the liver has remained largely unexplored. Therefore, we investigated NAFLD-induced drug metabolism mediated by CYP by quantitative toxicoproteomics analysis. After administration of a methionine-choline deficient (MCD) diet to induce development of NAFLD, tandem mass tags-based liquid chromatography-tandem mass spectrometry analysis was conducted to investigate the dynamics of hepatic proteins. A total of 1295 proteins were identified, of which 934 were quantified by proteomic analysis. Among these proteins, 21 proteins were up-regulated and 51 proteins were down-regulated by the MCD diet. Notably, domain annotation enrichment using InterPro indicated that proteins related to CYPs were significantly decreased. When we investigated CYP activity using in vivo and in vitro CYP cocktail assays, most CYPs were significantly decreased, whereas CYP2D was not changed after administration of the MCD diet. In conclusion, we identified significantly altered levels of CYPs and their activities induced by the MCD diet and confirmed the NAFLD-induced drug metabolism by pharmacokinetic analysis.NAFLD-induced drug metabolism was investigated by comparative toxicoproteomics.Among 934 quantified proteins, 21 were up-regulated, and 51 were down-regulated.Domain annotation enrichment indicated CYPs were significantly decreased.The decreased CYP activities were confirmed by in vivo and in vitro assays.Our data provides understanding of the drug-interaction in NAFLD patients.