Cyclophosphamide (CYP) is a chemotherapeutic agent used to treat cancers, but its therapeutic uses are limited due to its hepatotoxicity. Consequently, the current work aimed to investigate the potential hepatoprotective impact of quercetin (QRC) nanoparticles against CYP-induced liver damage. Twenty albino rats were divided into four even groups. Group (A) was carried out as the control group. Group (B) injected a single dose of CYP (200 mg/kg) intraperitoneally. Group (C) received orally nano quercetin at a dosage of 50 mg/kg for 10 days, they were also given a single dose of CYP i.p. and Group (D) was given nano-QRC orally at a dose of 50 mg/kg for 10 consecutive days. Samples were collected 24 hours after CYP injection for biochemical, histopathological and ultrastructural examinations. CYP significantly elevated the AST, ALT and MDA levels and substantially reduced the total antioxidant capacity (TAOC) in comparison to the control group. Moreover, the nano-QRC + CYP treated group significantly declined the raised AST and MDA levels, and significantly raised the diminished TAOC as compared to CYP treated group. Histopathological examination revealed a severe degree of congestion and dilatation of the central vein, perivascular fibrosis and hepatocellular vacuolation and necrosis were recorded in CYP treated group. However, only mild hepatic lesions were observed in nano-QRC + CYP treated group. It could be concluded that the administration of nano-QRC ameliorated the hepatic damage induced by CYP via its antioxidant activity.