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Abstract Tissue regeneration requires tight control of immune cell behavior, yet the mechanisms that restrain immune-driven regenerative responses remain poorly defined. Here, we identify the rhomboid intramembrane serine protease Rhbdl2 as a critical regulator of regeneration in zebrafish. We generatedrhbdl2mutants by CRISPR-Cas9 and found that it does not affect normal development, but triggers enhanced regenerative growth following injury, accompanied by increased macrophage accumulation at the wound site, which is accompanied by increased early apoptosis and proliferation. Proteomic analyses reveal increased Rac2 protein levels inrhbdl2mutants, indicating dysregulated immune signaling. Functionally, Rac2 morpholino oligonucleotides-mediated knockdown inrhbdl2mutant larvae suppresses the elevated macrophage recruitment and enhanced tissue regenerative phenotype. Together, these findings uncover Rhbdl2 as an immune checkpoint that constrains macrophage-driven enhanced regeneration, with vast implications for inflammatory disease, fibrosis, and tumor–immune interactions.