Ethnopharmacological relevance: Diabetic nephropathy (DN) is an acute and serious diabetic complication characterized by renal hypertrophy and renal fibrosis with the expansion of extracellular matrices. Diabetic nephropathy has become a major cause of end-stage kidney disease. Sanziguben Granule (SZGB) is a compound prescription which has been widely applied in clinical medicine for the prevention and treatment of diabetic nephropathy as well as for acute and chronic kidney injuries. However, the mechanism of protective effects of SZGB in DN remains unclear. Materials and methods: In this research, we investigated the effects of SZGB on renal interstitial fibrosis, antioxidant proficiency, and apoptosis in streptozotocin (SCZ)-induced diabetic rats. Diabetic rats were prepared by performing a right uninephrectomy along with a single intraperitoneal injection of STZ. Rats were divided into six groups including sham, DN, SZGB-D, SZGB-Z, SZGB-G and fosinopril. SZGB and fosinopril were given to rats by gavage for 12 weeks. Samples from urine, blood and kidneys were collected for biochemical, histological, immunohistochemical and western blot analyses. Results: We found that rats treated with SZGB showed reduced 24-h urinary protein excretion along with reduced serum total cholesterol (TC) and triglyceride (TG) levels. SZGB was also shown to prevent the disruption of catalase activity and reduce serum urea, creatinine, and renal malondialdehyde while increasing glutathione levels. Moreover, SZGB administration markedly improved the expression levels of E-cadherin, 4-HNE, Nrf2, HO-1, and Bcl-2, while it decreased the expression levels of Vimentin, alpha-SMA and Cleaved caspase3 in the kidneys of diabetic rats. The renoprotective effects of SZGB was believed to be mediated by its antioxidant capacity, and SZGB treatment attenuated renal fibrosis through stimulating the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Conclusions: Therefore, it is suggested that SZGB can restrain epithelial-mesenchymal transition (EMT) through stimulating the Nrf2 pathway, which improves renal interstitial fibrosis in DN.