The present study examines the detailed mechanism of the beneficial action of Zingiberene (ZBN) on streptozotocin-induced diabetic nephropathy. Diabetes was induced in adult male albino rats of the Wistar strain, weighing 180-200 g, by administration of streptozotocin (60 mg/kg of body weight) intraperitoneally. Animals were divided into the following four groups (n=6): control, ZBN control (50 mg/kg BW), diabetic control, and diabetic + ZBN (50 mg/kg BW) respectively. Diabetic animals exhibited elevated blood glucose levels, blood urea nitrogen, serum creatinine, and urine albumin levels in diabetic rats. Treatment with ZBN ameliorated hyperglycemia and kidney functions in diabetic rats. Chronic hyperglycemia significantly in-creased malondialdehyde, and decreased antioxidant levels in STZ-induced diabetic rats. ZBN significantly attenuated oxidative stress and enhanced antioxidant defenses in the diabetic kidney. Further, ZBN treatment significantly suppressed the renal protein expression of phosphorylated (p)-p38 mitogen-activated protein kinase (MAPK), p-c-Jun N-terminal kinase, and p-extracellular signal-regulated kinase 1/2 protein expression in STZ-induced diabetic rats, as determined by western blotting. This work provides compelling evidence that ZBN protects against diabetes-induced kidney damage by reducing oxidative stress by blocking the MAPK signaling pathway.