N-methyladenosine (mA) RNA modification, a dynamic and reversible process, is essential for tissue development and pathogenesis. However, the potential involvement of mA in the regulation of cardiomyocyte (CM) proliferation and cardiac regeneration remains unclear. In this study, we aimed to investigate the essential role of mA modification in heart regeneration during postnatal and adult injury. In this study, we identified the downregulation of mA demethylase ALKBH5, an m6A "eraser" that is responsible for increased mA methylation, in the heart after birth. Notably, knockout mice exhibited decreased cardiac regenerative ability and heart function after neonatal apex resection. Conversely, forced expression of ALKBH5 via adeno-associated virus-9 (AAV9) delivery markedly reduced the infarct size, restored cardiac function and promoted CM proliferation after myocardial infarction in juvenile (7 days old) and adult (8-weeks old) mice. Mechanistically, ALKBH5-mediated mA demethylation improved the mRNA stability of YTH N-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). The modulation of ALKBH5 and YTHDF1 expression in human induced pluripotent stem cell-derived cardiomyocytes consistently yielded similar results. Taken together, our findings highlight the vital role of the ALKBH5-mA-YTHDF1-YAP axis in the regulation of CMs to re-enter the cell cycle. This finding suggests a novel potential therapeutic strategy for cardiac regeneration.