<p>Cyclophosphamide, an extensively utilized alkylating agent in oncological therapies, is correlated with considerable hepatotoxicity, particularly following prolonged administration or instances of overdose. Esculetin, a phytochemical recognized for its therapeutic attributes, has exhibited potential in the management of a variety of diseases. This investigation assessed the hepatoprotective efficacy of esculetin in countering cyclophosphamide-induced hepatic damage in a rodent model. A total of thirty-six male Wistar albino rats were randomly allocated into six distinct groups: control, cyclophosphamide-treated, esculetin (50&#xa0;mg/kg/day) in conjunction with cyclophosphamide, esculetin (100&#xa0;mg/kg/day) alongside cyclophosphamide, silymarin (100&#xa0;mg/kg/day) in combination with cyclophosphamide, and esculetin (100&#xa0;mg/kg/day) administered alone. Treatment protocols were conducted over a span of 10&#xa0;days, with cyclophosphamide being administered on the 8th day, and the animals were euthanized on the 11th day. Biochemical markers of liver function, antioxidant capacity, and histopathological alterations were evaluated, in addition to an immunohistochemical analysis of NRF2 and NF-κB expression. The results demonstrated that cyclophosphamide elicited significant hepatotoxicity, as indicated by deviations in biochemical and histopathological parameters. Pre-treatment with esculetin effectively alleviated these alterations, revealing its protective capabilities via the modulation of oxidative stress, inflammatory responses, and apoptotic pathways. These outcomes imply that esculetin may have the potential to act as a therapeutic agent against cyclophosphamide-induced hepatic toxicity.</p> Graphical Abstract <p></p>