Hypertrophic cardiomyopathy (HCM) is a heterogeneous myocardial disease characterized by myocardial hypertrophy, myocardial mechanical and electrical activity obstacles. This study aimed to explore the relationship between YAP2 (Yes-associated protein 2) and HCM and clarify a signaling path about the pathogenesis of HCM. Our study confirms that YAP2 can promote myocardial cell hypertrophy at the molecular level (myocardial lineage cell H9C2), organ level (clinical specimens of human HCM), and an animal model (a mouse model of HCM with cardiac-specific transgenic and knockout YAP2). The detailed molecular mechanisms linking YAP2 to cardiomyocyte hypertrophy and HCM were investigated. This study proved that YAP2, as the final reaction factor in Hippo pathways, influences Akt1 activity to affect the downstream genes, which participate in the formation of HCM by promoting myocardial cell proliferation and cardiac hypertrophy.