We show here that AP-1 transcription factor genes are upregulated in border zone cardiomyocytes (CMs) following cryoinjury. Furthermore, using CM-specific dominant-negative approaches, we found that AP-1 contributes to chromatin accessibility changes in regenerating CMs and that AP-1 is essential for multiple aspects of CM regeneration, including dedifferentiation, proliferation, sarcomere disassembly, and invasion of the injured area. Notably, we found that the AP-1 response largely differs in regenerative zebrafish versus nonregenerative mouse CMs and that overexpression of Junb and Fosl1 in mammalian CMs can promote hallmarks of CM regeneration in vitro.