Aim: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, The potential and significance of clinical transformation of Sop should be broadened and it should be firmly supported as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure. Methods: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) hypertrophy model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At one week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination.Results: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulated. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy. Conclusion: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.