The inability of the adult mammalian heart to regenerate following injury represents a substantial barrier in cardiovascular medicine. We recently identified a brief window during post-natal development when the mammalian heart retains significant regenerative potential following amputation of the ventricular apex. However, one major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-day-old mice by permanent ligation of the left anterior descending coronary artery, and found that this results in extensive myocardial necrosis and systolic dysfunction at day 3 post-MI. Remarkably, the neonatal heart mounted a robust regenerative response resulting in full functional recovery within 21 days. Neonatal heart regeneration was associated with a robust induction (6-fold) of cardiomyocyte proliferation. Genetic lineage tracing of cardiomyocytes from Myh6-MerCreMer transgenic mice demonstrated that the majority of regenerated cardiomyocytes following neonatal MI were derived from pre-existing cardiomyocytes rather than from a stem cell population. The molecular mechanisms that regulate neonatal cardiac regenerative capacity are not understood but we have recently identified a large family of microRNAs, known as the miR-15 family, which regulate postnatal mitotic arrest of cardiomyocytes. Transgenic over-expression of miR-195, a member of the miR-15 family, was sufficient to impair the neonatal cardiac regenerative response and was associated with increased fibrosis and reduced cardiomyocyte proliferation. Finally, pharmacological inhibition of the miR-15 family by administration of locked nucleic acid-modified antimiRs from an early post-natal age until adulthood induced myocyte proliferation in the adult heart and improved left ventricular systolic function following ischemia-reperfusion injury. These findings indicate that the neonatal mammalian heart can regenerate following myocardial infarction and that the miR-15 family contributes to postnatal loss of cardiac regenerative capacity in mammals.