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Background Prostaglandin E2 has long been known to be an immune modulator. It is released after tissue injury and plays a role in modulating macrophage activities, which are essential for tissue regeneration. However, the involvement of prostaglandin E2 receptor 2 (EP2)–dependent regulation of macrophages in postischemic heart is unclear. This study aims to evaluate the role of EP2 in damaged heart. Methods and Results The effect of EP2 in postischemic heart was evaluated using EP2‐deficient transgenic mice. We demonstrated that cardiac function was worse after myocardial injury on loss of EP2. Furthermore, EP2 deficiency also altered proinflammatory response and resulted in a defect in macrophage recruitment to the injured myocardium. Transcriptome analysis revealed that the expression of erythroid differentiation regulator 1 (Erdr1) was significantly induced in EP2‐deficient macrophages. Knocking down Erdr1 expression restored migration ability of EP2‐deficient cells both in vitro and in vivo. By using a genetic fate‐mapping approach, we showed that abolishment of EP2 expression effectively attenuated cell replenishment. Conclusions The EP2‐dependent signaling pathway plays a critical role in regulating macrophage recruitment to the injured myocardium, thereby exerting a function in modulating the inflammatory microenvironment for cardiac repair.