Background: Diabetic nephropathy has become the most common cause of morbidity and mortality in diabetic patients. Therefore, there is an urgent need for more effective and safer drugs for use in this condition. Purpose: The aims of this study were to investigate the ameliorative effects of total saponin of Dioscoreae hypoglaucae rhizoma (TSD) on diabetic nephropathy and to explore the potential underlying mechanism(s). Methods: Rats with streptozotocin-induced diabetes were orally treated with TSD at 40, 80, and 160 mg/kg/day for 12 weeks. At the end of the treatment, blood, urine, and kidneys were collected for biochemical and histological examination. Results: The results demonstrated that TSD significantly decreased the fasting blood glucose, glycosylated hemoglobin, urinary protein,... serum creatinine, and blood urea nitrogen levels in diabetic rats. The results of histological examinations showed that TSD ameliorated glomerular and tubular pathological changes in diabetic rats. Furthermore, TSD significantly prevented oxidative stress and reduced the renal levels of advanced glycation end products, transforming growth factor-β1, connective tissue growth factor, and tumor necrosis factor-α. Conclusion: This study demonstrated the renoprotective effects of TSD in experimental diabetic nephropathy via a number of different mechanisms.