Oxidative stress plays a major role in the development and progression of diabetic nephropathy (DN). In this study, the potential protective effect of ginger (Zingiber officinale) rhizome extract on hyperglycemia-induced oxidative stress, inflammation and apoptosis was investigated. An experimental diabetic rat model was induced by intraperitoneal injection of streptozotocin. Diabetic rats were treated orally with 400 or 800 mg/kg/day Z. officinale extract for six weeks. Diabetic animals exhibited elevated blood glucose levels and glycated hemoglobin (HbA1c) with altered lipid profile. Blood urea nitrogen, serum creatinine and urea, and urine albumin levels were significantly increased in diabetic rats. Treatment with Z. officinale ameliorated hyperglycemia, hyperlipidemia and kidney function. In addition, Z. officinale minimized the histological alterations in the kidney of diabetic rats. Chronic hyperglycemia resulted in a significant increase in malondialdehyde, protein carbonyl, pro-inflammatory cytokines, cytochrome c and caspase-3 in the kidney of rats. Z. officinale extract significantly attenuated oxidative stress, inflammation and apoptosis, and enhanced antioxidant defenses in the diabetic kidney. In conclusion, this study strongly suggests that Z. officinale rhizome extract exerts a protective role against diabetes-induced renal injury by ameliorating oxidative stress, inflammation and apoptosis.