The underlying mechanisms remain enigmatic, although divergence striking across ontogeny and phylogeny. Loss of regenerative potential correlates with polyploidization and cardiomyocyte cell-cycle arrest as well as the evolution of postnatal endothermy. We show that diploid cardiomyocyte prosperity across 41 species adheres to Kleiber&rsquo law–the 3/4-power law scaling of metabolism with bodyweight–also correlates with standard metabolic rate, body temperature, and serum thyroxine level. Inactivation of thyroid hormone signaling reduces mouse cardiomyocyte polyploidization, delays exit, and retains cardiac regenerative possible in adults. Conversely, zebrafish heart regeneration is inhibited by exogenous thyroid hormones. Therefore, our findings suggest that thyroid hormones that are increasing trigger loss of heart regenerative capacity in mature mammals and may be a trade-off for its acquisition of endothermy.