The use of cyclophosphamide as a chemotherapy drug for treatment of many malignancies is mostly accompanied by hepatotoxicity. So, the present study aimed to investigate the potential ameliorative impact of the Egyptian bitter orange peel (BOP) or Citrus aurantium L. against hepatotoxicity of cyclophosphamide in rats. Total and differential polyphenolic content by HPLC of BOP as well as its antioxidant activity were determined. Then, a biological experiment was done including four groups of male adult Wistar rats. A control negative group injected with saline, a group that was injected with saline and fed on basal diet supplemented with 20% BOP and two groups that were injected intraperitoneally by 40 mg/kg body weight of cyclophosphamide for four successive days to induce hepatotoxicity; one of them was control positive fed on basal diet and the other was fed on 20% bitter orange peel to evaluate its hepatic ameliorative effect. Results revealed the presence of seventeen polyphenolic compounds in the BOP methanolic extract and also, that it has a relatively high antioxidant activity. An elevation in the serum ALT and AST activities and in hepatic MDA and TNF-α concentrations, while a reduction in the serum total protein, albumin, A/G ratio and in hepatic GSH was detected for the cyclophosphamide-injected group compared to the control negative. All these alterations were restored to near the normal values of the control negative group in the cyclophosphamide-injected group that received BOP. Histopathological examination confirmed the biochemical findings. In conclusion, bitter orange peel has a potent antioxidant activity that enable it to counteract hepatotoxicity accompanied to cyclophosphamide therapy.