ObjectiveTo investigate the effects of Guizhi Fulingwan on oxidative stress and renal fibrosis in diabetic mice based on the nuclear factor E₂-associated factor 2/antioxidant response element （Nrf2/ARE） pathway， and to explore its mechanism of action. MethodA diabetic mouse model was established by feeding high-fat diet combined with intraperitoneal injection of streptozotocin. The diabetic mice were divided into a model group， a metformin group （250 mg·kg^-1）， and Guizhi Fulingwan low， medium， and high dose groups （400.4， 800.8， 1 601.6 mg·kg^-1）， with 10 mice in each group. Another 10 mice were included in a normal group. The treatment was conducted continuously for 8 weeks. Body mass and blood glucose were recorded， and the renal index was calculated. Triglyceride （TG）， total cholesterol （TC）， urea nitrogen （BUN）， serum creatinine （SCr）， superoxide dismutase （SOD）， and malondialdehyde （MDA） levels were measured. Pathological changes in renal tissues were observed using Hematoxylin-eosin， periodate-Schiff， and Masson staining. The protein levels of α-smooth muscle actin （α-SMA）， fibronectin （FN）， and transforming growth factor-β₁ （TGF-β₁） were detected by immunohistochemistry. The protein levels of Nrf2， Kelch-like ECH-associated protein 1 （Keap1）， SOD1， NAD（P）H single-nucleotide oxidase 1 （NQO1）， and heme oxygenase-1 （HO-1） were detected by Western blot. ResultCompared with the normal group， the model group showed elevated glucose， renal index， TG， TC， BUN， and SCr levels， thickened glomerular basement membrane， increased collagen fibers in renal tissues， decreased SOD activity， elevated MDA content， increased protein levels of FN， TGF-β₁， α-SMA， and Keap1， and decreased protein levels of Nrf2， SOD1， NQO1， and HO-1 （P<0.01）. Compared with the model group， the Guizhi Fulingwan and metformin groups showed reduced blood glucose， renal index， TG， TC， BUN， and SCr levels， improved renal histopathological injury， significantly increased SOD activity， significantly reduced MDA content， reduced protein levels of FN， TGF-β₁， α-SMA， and Keap1， and increased protein levels of Nrf2， SOD1， NQO1， and HO-1 （P<0.05， P<0.01）. ConclusionGuizhi Fulingwan can improve oxidative stress and inhibit renal fibrosis， and its mechanism may be related to the activation of the Nrf2/ARE signaling pathway.