Myocardial infarction results in compromised myocardial function and heart failure owing to insufficient cardiomyocyte self-renewal1. Unlike many vertebrates, mammalian hearts have only a transient neonatal renewal capacity2. Reactivating primitive reparative ability in the mature mammalian heart requires knowledge of the mechanisms that promote early heart repair. By testing an established Hippo-deficient heart regeneration mouse model for factors that promote renewal, here we show that the expression ofPitx2is induced in injured, Hippo-deficient ventricles.Pitx2-deficient neonatal mouse hearts failed to repair after apex resection, whereas adult mouse cardiomyocytes withPitx2gain-of-function efficiently regenerated after myocardial infarction. Genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. A subset of Pitx2 target genes was cooperatively regulated with the Hippo pathway effector Yap. Furthermore, Nrf2, a regulator of the antioxidant response3, directly regulated the expression and subcellular localization ofPitx2.Pitx2mutant myocardium had increased levels of reactive oxygen species, while antioxidant supplementation suppressed thePitx2loss-of-function phenotype. These findings reveal a genetic pathway activated by tissue damage that is essential for cardiac repair.