In the present study, using both overexpression and knockout mouse and overexpression cell models, we first time demonstrated that FKBP12.6 protects hearts from AngII‐induced hypertrophy in vivo and in vitro, seen as lack of FKBP12.6 gene markedly aggravate AngII‐induced cardiac hypertrophy, whereas cardiac‐specific overexpression of FKBP12.6 prevents the hypertrophic response to AngII. Here, FKBP1B is linked to cardiac hypertrophy.