In this study, we found that REGγ was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and depletion of REGγ in mice after TAC operation results in a massive inhibition of reactive oxygen species (ROS) accumulation and protein phosphatase 2A catalytic subunit α (PP2Acα) decay in heart and ameliorates pathological cardiac hypertrophy in a PP2Acα–FoxO3a–SOD2-dependent manner. This evidence concerns the gene FOXO3 and cardiac hypertrophy.