To investigate the effects and possible mechanisms of total flavonoids of Herba Epimedii (TFE) on renal fibrosis in natural aging rats,18-month-old SD rats were randomly divided into natural aging group,low- (10 mg/kg) and high- (40 mg/kg) dose of TFE groups,the other 2-month-old SD rats as young control group.After 4 months of administration,the morphology of kidney was observed by HE staining,and the collagen fibers of kidney were observed by Masson staining,the activity of SOD and the content of MDA in kidney tissues were detected by biochemical enzymatic methods,the expression of αSMA protein in kidney tissues was observed by immunohistochemistry.Real-time PCR and Western blot were adopted to detect the mRNA level and protein expression of TGF-β1 and Smad3.The results showed that TFE (low- and high-dose) improved the damage of renal tissue histomorphology,reduced the number of inflammatory cells and collagen fibers.SOD activity was increased and MDA content was decreased in renal tissues.It also decreased the protein expression of αSMA in kidney,down-regulated the mRNA and protein expression of TGF-β1 and Smad3.Total flavonoids of Herba Epimedii can protect kidney from fibrosis in natural aging rats,and its mechanism may be related to the regulation of TGF-β1/Smad3 signaling pathway.