Introduction: Cancer is one of the lethal diseases in the global world. Proliferation of cancer cells is commonly inhibited by chemotherapeutics. Cyclophosphamide (CP) is an alkylating chemotherapeutic agent often used for treatment of various types of cancers, but it is full of side effects which in turn lead to organ toxicity. Zingerone, a polyphenolic alkanone found in ginger, has strong antioxidant potential and causes extensive scavenging of free radicals and offers defense against oxidative stress. Twenty-four adult male Wistar rats were divided into four groups, six rats in each group. Materials and Methods: Group I (control), Group II (CP, 2 mg/kg bwt), Group III (cotreatment with zingerone at the dose of 50 mg/kg bwt and CP at the dose of 2 mg/kg bwt), and Group IV (pretreatment of zingerone at the dose of 50 mg/kg bwt for 7 days and CP at the dose of 2 mg/kg bwt for next 7 days). Results: CP significantly increased the level of hepatic marker enzymes such as alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, drastically caused alteration in lipid profile and deficiency in antioxidant defense mechanism by decreasing the activities of antioxidant enzymes such as catalase, glutathione, glutathione-S-transferase, and glutathione peroxidase. This was accompanied by subsequent increase in lipid peroxidation, nitrite production, and marked DNA damage. Conclusion: The restoration of hepatic markers, amelioration of lipid profile, and improvement of antioxidant status and DNA damage by pre- and co-treatment with zingerone clearly indicate the ameliorative potential of zingerone against CP-induced organ toxicity and oxidative stress. The protective potential of zingerone may be attributed to its strong antioxidant activity.