In this study, we are the first to provide the evidence that CD38 deficiency markedly alleviated Ang‐II‐induced cardiac hypertrophy in vitro and in vivo, through activating the SIRT3‐FOXO3‐mediated anti‐hypertrophic signalling pathway and suppressing the Ca2+–calcineurin–NFAT‐mediated prohypertrophic pathway. Here, SIRT3 is linked to cardiac hypertrophy.