Abstract: Objective: To explore the potential mechanism of Huoxue Lishui compound in treating spontaneous hypertension, and to provide basic theoretical and experimental basis for clarifying the efficacy of Huoxue Lishui compound in treating spontaneous hypertension based on TGF-β1-Smads signaling pathway. Methods: Male spontaneously hypertensive rats aged 14 weeks were randomly divided into normal control group, model group, captopril group, low-dose group of Huoxue Lishui compound and high-dose group of Huoxue Lishui compound (n=20). The blood pressure of rats was monitored by tail artery noninvasive blood pressure meter. Hematoxylineosin (HE) staining was used to detect the ultrastructure of rat aorta. Immunohistochemical staining was used to detect the expression of transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1),Ⅰ and Ⅲ collagen in aorta of each group. Immunoprecipitation was used to detect the expression of Smad2-Smad3 complex and Smad2-Smad3-Smad4 complex in each group. The expression of TGF-β1, Smad2, Smad3, Smad4, Smad7 and CTGF in serum of rats was detected by enzyme linked immunosorbent assay (ELISA). Results: Compared with the normal control group, the blood pressure of model group was increased (P＜0.01). Compared with the model group, the blood pressure of captopril group was decreased from the 2nd week to the 4th week after treatment (P＜0.01), the blood pressure of low-dose group of Huoxue Lishui compound was decreased from the 3rd week to the 4th week after treatment (P＜0.05, P＜0.01), and the blood pressure of high-dose group of Huoxue Lishui compound was significantly decreased from the 1st week to the 4th week after treatment (P＜0.01). Huoxue Lishui compound intervention alleviated the pathological changes of spontaneously hypertensive rats and improved the vascular remodeling of hypertension. The expression of TGF-β1, CTGF, TIMP1, Ⅰ and Ⅲ types of collagen in the model group was significantly increased, while the expression of TGF-β1, CTGF, TIMP1, Ⅰ and Ⅲ types of collagen in the captopril group, highdose group of Huoxue Lishui compound and low-dose group of Huoxue Lishui compound was decreased. In particular, the reduction of captopril group and high-dose group of Huoxue Lishui compound was particularly obvious. The expression of SMad2-Smad3, Smad2, Smad3 and Smad4 in the captopril group, high-dose group of Huoxue Lishui compound and low-dose group of Huoxue Lishui compound was decreased compared with the model group. In particular, the expression of SMad2-Smad3, Smad2, Smad3 and Smad4 in the captopril group and high-dose group of Huoxue Lishui compound was significantly reduced compared with those in the model group. Compared with the model group, the expression of TGF-β1, Smad2, Smad3 and Smad4 in the low-dose group of Huoxue Lishui compound was significantly decreased (P＜0.05), while the expression of Smad7 and CTGF was not statistically significant (P＞0.05). Compared with the model group, the expression of TGF-β1, Smad2, Smad3, Smad4 and CTGF in the captopril group was significantly decreased (P＜0.05 or P＜0.01), while the expression of Smad7 was significantly increased (P＜0.05). The expression of TGF-β1, Smad2, Smad3, Smad4 and CTGF was decreased (P＜0.05 or P＜0.01), and Smad7 expression was increased (P＜0.05) in the the high-dose group of Huoxue Lishui compound. Conclusion: Huoxue Lishui compound can effectively treat spontaneous hypertension through TGF-β1-Smads signaling pathway intervention, which provides theoretical basis for clinical treatment and related research of spontaneous hypertension in the later stage.