Vancomycin (VCM) is a glycopeptidic broad-spectrum antibiotic against methicillin-resistant Staphylococcus aureus, though it has some adverse effects, including nephrotoxicity, that limit its usefulness. Zingerone (ZO), a component of dry ginger root, has several pharmacological activities due to its antioxidant, anti-inflammatory and antiapoptotic properties. The aim of this study was to determine the therapeutic efficacy of ZO against VCM-induced oxidative stress, inflammation, apoptosis and kidney aquaporin 1 (AQP1) levels in rats. Intraperitoneal administration of VCM (200 mg/kg body weight) for seven days increased kidney lipid peroxidation and decreased antioxidant enzyme activities, including kidney superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). VCM increased serum creatinine and urea levels and induced histopathological changes while causing a decrease in AQP1 protein level. VCM also increased the levels of the inflammatory markers nuclear factor kappa B (NF-κB), B-cell lymphoma-3(Bcl-3), interleukin-1β (IL-1β), interleukin-33 (IL-33), tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) and cyclooxygenase-2 (COX-2). Moreover, it activated the apoptotic pathway by increasing the expression levels of p53, Bcl-2 associated X protein (Bax), cysteine aspartate specific protease-3 (caspase-3) and 8-hydroxy-2′-deoxyguanosine (8−OHdG), which is a marker of oxidative DNA damage. Treatment with ZO (25 and 50 mg/kg body weight) at both doses prevented nephrotoxicity by ameliorating the histopathological alterations, oxidative stress, inflammation, apoptosis, oxidative DNA damage and renal AQP1 levels. The findings of the present study suggested that ZO attenuates VCM-induced nephrotoxicity.