Carbon tetrachloride (CCl4) is a notorious environmental pollutant known for its toxicity. The aim of the present study was to evaluate the possible protective effects of aqueous pomegranate peel extract (PPE) against CCl4 induced nephrotoxicity in mice. Adult male mice were divided into four groups: Group one was used as the control; Group two was treated with a daily oral dose of PPE (400 mg/kg) for 15 days; the third group was intraperitoneally injected with a dose (1 ml/kg) of CCl4 twice a week for two weeks; and the final group was injected with the same dose of CCl4 twice a week concomitantly with a daily oral dose of PPE (400 mg/kg). Biochemical and histopathological data were analyzed along with the gene expression levels of the antioxidant enzymes and immunohistochemistry of the kidney tissue. CCl4 resulted in a significant increase in the serum urea and creatinine levels with detectable degenerative changes in the Bowman's capsule and glomerulus, with cells exhibiting vacuolization and evidence of necrosis. Co-administration of animals with CCl4 and PPE resulted in improved biochemical and histopathological conditions. Similarly, increased production of the Caspase-3 and collagen fibers were reduced in mice treated with PPE. Quantitative analysis of superoxide dismutase, catalase and glutathione peroxidase further accentuated the effects of PPE treatment significantly improving the conditions of the CCl4-administered group. The results of the present study demonstrate that the phenolic derivative rich PPE is a potent nephroprotective agent and suppresses CCl4-induced nephrotoxicity in mice.