Background:Chemically induced cirrhotic animal models are commonly used. However, they have limitations such as high mortalities and low yield of cirrhotic animals that limit their uses.Aims:To overcome limitations of the chemically induced cirrhotic animal model via combined administration of methotrexate (MTX) with CCl4and decrease their commonly used doses depending on the proposed synergetic cirrhotic effect.Methods:Rats were divided into six groups: normal (4 weeks), normal (8 weeks), MTX, CCl4(4 weeks), CCl4(8 weeks), and MTX + CCl4(4 weeks) groups. Animals’ hepatic morphology and histopathological characterization were explored. Hepatic Bcl2 and NF-κB-p65 tissue contents were determined using the immunostaining technique, and hepatic tissue damage, oxidative status, and inflammatory status biochemical parameters were determined.Results:CCl4+ MTX combined administration produced prominent cirrhotic liver changes, further confirmed by a substantial increase in oxidative stress and inflammatory parameters, whereas mortalities were significantly lower than in other treated groups.Conclusion:The present study introduced a new model that can significantly improve the major limitations of chemically induced cirrhotic animal models with new pathological features that mimic human cirrhosis. Compared to other chemically induced methods, the present model can save time, cost, and animal suffering.