In this study, we have demonstrated that THC treatment significantly increased the expression of SIRT1 and deacetylated SOD2 both in vitro and in vivo, thus prevented cardiomyocytes against oxidative damage and inhibited the ROS-induced TGFβ1/Smad3 profibrotic signaling pathway, which finally alleviated myocardial hypertrophy and cardiac dysfunction in DCM. Here, SMAD3 is linked to cardiac hypertrophy.