The benchmark of this study is to evaluate the antioxidant protective efficiency of Diosmin-Hesperidin combination, a natural citrus flavone of hesperidin derivative on heavy metals intoxication and Oxidative stress-induced damage in Wistar albino rats. Oral doses of diosmin-hesperidin in rats (200 and 100 mg/kg body weight, respectively) for a month (every other day) prior to heavy metals intoxication. Evaluation of the protective and antioxidant effects of the combination of diosmin and hesperidin, various Rt-PCR estimations, biochemical estimations, histopathological alterations as well as comet assay and caspase-3 activity for assessment of apoptosis were performed. Results indicated that heavy metals intoxication-induced decline in the levels of liver tissue P53 gene expression and increase of liver tissues of the apoptotic caspase-3 gene, also induced decline in the levels of liver tissue antioxidant parameters (SOD, GPx, and GSH), increased lipid peroxidation (MDA), DNA damage and apoptosis, these parameters were improved by pre-administration of diosmin+hesperidine. Diosmin+hesperidine dose (200 and100 mg/kg body wt. respectively) restored the p53 and caspase-3 genes near-normal values, antioxidant status to near normal and reduced lipid peroxidation, DNA, and tissue damage. These results were confirmed by histopathological examinations, which showed that pre-administration of diosmin+hesperidine protected the liver of albino rats against heavy metals intoxication-induced damage. Hence, it has been illustrated that diosmin+hesperidine might be an effective antioxidant and protector against heavy metals intoxication-induced damage in rats. Moreover, the diosmin+hesperidine alone pretreated group did not show any biochemical alterations, fold change of P53 or caspase-3 genes or DNA damage indicating the protective nature of the drug.