Myocardial remodeling, which occurs in the final stage of cardiovascular diseases such as hypertension, can ultimately result in heart failure. However, the pathogenesis of myocardial remodeling remains incompletely understood, and there is currently a lack of safe and effective treatment options. Salidroside, which is extracted from the plant Rhodiola rosea, shows remarkable antioxidant and anti-inflammatory characteristics. The purpose of this investigation was to examine the cardioprotective effect of salidroside on myocardial remodeling, and clarify the associated mechanism. Salidroside effectively attenuated cardiac dysfunction, myocardial hypertrophy, myocardial fibrosis, and cardiac inflammation, as well as renal injury and renal fibrosis in an animal model of deoxycortone acetate (DOCA)-salt-induced myocardial remodeling. The cardioprotective effect of salidroside was mediated by inhibiting the endothelin 1 and PI3K/AKT/NFκB signaling pathways. Salidroside was shown to inhibit the expression of endothelin1 in the hearts of mice treated with DOCA-salt. Additionally, it could prevent cardiomyocyte hypertrophy induced by endothelin-1 stimulation. Furthermore, Salidroside could effectively inhibit the excessive activation of the PI3K/AKT/NFκB pathway, which was caused by DOCA-salt treatment in mouse hearts and endothelin 1 stimulation in cardiomyocytes. Our study suggests that salidroside can be used as a therapeutic agent for the treatment of myocardial remodeling.