Objective To investigate the activities of major CYP enzymes in rat models of nonalcoholic fatty liver(NAFL) established by carbon tetrachloride (CCl₄ ) for various time periods and compare their activities with another NAFL model established by a high fat diet. Methods The experimental rats were divided into two different model groups with corresponding vehicle groups. The model groups either received a subcutaneous injection of 40% CCl₄ twice a week for 9 weeks (CCl₄ model) or continuous administration of a high fat diet for 9 weeks (high fat model). Histopathological observation, liver lipid content, and liver index (liver-to-brain ratio) were determined to confirm the rat NAFL modeling.Blood biochemical ALT and AST were measured, and the main CYP enzyme activities were measured. Results Histopathological findings of the two models were consistent with NAFL characteristics, and there was a significant increase in intrahepatic lipid content and the liver-to-brain ratio. The activities of the main CYP enzymes (except CYP2B6) in the NAFL model established by CCl₄ was significantly lower than those in the vehicle group ( P <0. 001), which was decreased over time. Both ALT and AST were increased significantly in the model group established by CCl₄ . There was no significant changes in the main CYP enzyme activities of the model established by high fat diet. The difference between the two models was significant ( P < 0. 001). Both ALT and AST were significantly elevated in the model group established by CCl₄ , but no increase was found in the model group established by high fat diet. Conclusions Activity of the main CYP enzymes in liver tissue can be used to verify the rat NAFL model established by CCl₄ or a high fat diet.