This study evaluated the potential of Punica granatum peel ethanol extract (PPEE) in attenuating the liver and kidney tissue injury induced by vancomycin (VM) treatment in rats. Fifty rats were distributed equally into five groups: control group, PPEE-administered group (100 mg/kg BW/day for 2 weeks; orally), VM-treated group (443.6 mg/kg BW, every alternate day for 2 weeks; intraperitoneally), pre-treated group, and concomitant-treated group. The biochemical response and the histopathology of the hepatic and renal tissue of the treated animals were assessed. The results showed that VM treatment induced substantial hepatotoxicity and nephrotoxicity, evidenced by a significant elevation in tissue injury and lipid oxidative (malondialdehyde) and inflammatory response (C-reactive protein) biomarkers, with lowered antioxidants and protein levels. Additionally, VM treatment induced various morphological, cytotoxic, vascular, and inflammatory perturbations as well as upregulation in the immune-expression of Caspase-3 and downregulation of BCL-2. Moreover, PPEE co-treatment was found to reduce the VM-induced toxicity by protecting the tissue against reactive oxygen species (ROS)–mediated oxidative damage, and inflammation as well as hinder the apoptotic cell death by modulating the expression of apoptosis-related proteins. Thus, we conclude that the PPEE administration showed more restoring efficacy when administered prior to VM medication.