【Abstract】Objective To investigate the therapeutic effect and underlying mechanism of Qishishenshu capsule on renal fibrosis in mice with early diabetic nephropathy (DN). Methods DN mouse model was established by multiple injection of streptozotocin (STZ). The mice were randomly divided into the normal group (NC), model group (DN) and Qishi group (QS)(0.9 g/kg/d), 8 mice in each group, gavaged continuously for 4 weeks, and fasting blood glucose (FBG) was measured weekly. 4 weeks later, urinary microalbumin creatinine ratio (UACR), serum creatinine (SCr) and blood urea nitrogen (BUN) were measured. Hematoxylin-eosin staining (HE staining), periodic acid-Schiff staining (PAS staining) and Sirius red staining were used to analyze renal pathological changes. Real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect the Message RNA (mRNA) levels of fibronectin (FN), collagen type I alpha 1 (Col1a1), and α-smooth muscle actin (α-SMA). Immunohistochemistry (IHC) and Western blot (WB) were performed to detect FN, collagen type I (Collagen I), collagen type III (Collagen III), α-SMA, Podocin, Nephrin and transforming growth factor-β1/SMAD family member2/3 (TGF-β1/Smad2/3) pathway-related proteins. Results Compared with the NC group, mice in the DN group showed significantly higher levels of FBG and UACR (P<0.001). Mesangial hyperplasia, basement membrane thickening and collagen deposition occurred in renal tissue. The mRNA levels of FN, Col1a1 and α-SMA were increased (P<0.05). Protein levels of Podocin and Nephrin were decreased (P<0.05). The levels of FN, Collagen I, Collagen III, α-SMA and TGF-β1/Smad2/3 pathway protein were increased (P<0.05). Compared with the DN group, the level of UACR in QS group was decreased (P<0.05), and renal pathological injury was alleviated. The mRNA levels of FN, Collagen1 and α-SMA were attenuated (P<0.05). The protein levels of Podocin and Nephrin were elevated (P<0.05). Protein levels of FN, Collagen I, Collagen III, α-SMA and TGF-β1/Smad2/3 pathway protein were also decreased (P<0.05). Conclusions Qishishenshu Capsules improved renal fibrosis in DN mice probably through the inhibition of TGF-β1/Smad2/3 signaling pathway.