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Background & aim: Cyclophosphamide (CP) is an immunosuppressive medication which is primarily used to manage and treatt of neoplasms, including breast cancer, lymphoma and Leukemia. CP as well possesses many side effects, including hepatotoxicity which leads to mitochondrial oxidative stress, cell death and hepatic necrosis. Empagliflozin (EMPA) is a Sodium-glucose cotransporter-2 inhibitor used to treat diabetes and has antioxidant activity. The present study was designed to investigate the effect of Empagliflozin on hepatotoxicity induced by cyclophosphamide in male rats. Methods: The present experimental study was conducted at the School of Medicine, Yasuj University of Medical Sciences in 2023. Twenty-four male Wistar rats were divided into four groups: control group, CP group, EMPA+CP group and CP+EMPA group. All groups were treated for 11 days. Moreover, blood samples were obtained and the liver was removed. Plasma levels of ALT, AST and ALP were measured. Homogenized liver tissue was used to measure malondialdehyde (MDA), Nitric Oxide (NO). Liver histology was also performed. The results were analyzed by one- way ANOVA and Tukey's Post Hoc test. Results: The results indicated that cyclophosphamide triggered a significant increase in the plasma level of AST, ALT enzymes and the level of NO and MDA metabolites in the liver tissue (p