Cyclophosphamide (CP), a chemotherapeutic agent, induces hepatotoxicity as one of its side effects. Therefore, the aim of the present study is to investigate the potential hepatoprotective effects of fullerene C₆₀ nanoparticles (C₆₀) against the high toxic dose of CP. Twenty five albino rats were randomly assigned to 5 groups (n=5 per group). Group 1 served as a control. Group 2 received 200mg/kg of CP once intraperitoneally, while group 3 treated with the same CP dose plus C₆₀ (4mgkg, orally) daily for 10days. Group 4 exposed CP and ZnCl₂ (4mgkg, orally) daily for 10days. Group 5 exposed to CP and co-treated with C₆₀ and ZnCl₂. One day after last treatment, blood and livers were collected for hematological, biochemical and histopathological investigations. C₆₀ normalized significantly RBCs, HB, PCV, WBCs and platelets numbers compared to CP-exposed rats. Moreover, liver enzymes namely ALT, AST and ALP revealed that CP elevated their levels and C₆₀ significantly (p<0.05) reduced them to basal levels. The level of oxidative stress marker namely, MDA was elevated upon CP exposure and normalized by C₆₀ treatment. In addition, antioxidant systems e.g. GSH, CAT and SOD were depleted from liver tissue due to CP toxicity these were recovered by C₆₀ administration. The hepatoprotective effects of C₆₀ on tested parameters were comparable with ZnCl₂ and neither additive nor synergistic effect was observed. Histopathogically, severe liver degeneration was recorded after CP treatment, however, only mild changes were observed after C₆₀ administration. Our data suggest that C₆₀ improves both blood and hepatic parameters altered by cyclophosphamide-induced toxicities. The current study is of clinical relevance particularly, application of C₆₀ as a monotherapy or in combination to ameliorate the CP side effects in cancer-treated patients.