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Myocardial infarction (MI) is the most common cause of cardiac injury, resulting in widespread and irreversible damage to the heart. The incidence of MI gives rise to the excessive production of inflammatory cytokines that further promotes myocardial dysfunction. Wnt/β-catenin signaling pathway is adversely activated during MI and plays an important role in the modulation of the inflammatory response following tissue injury. Huoxin pill (HXP) is a Traditional Chinese Medicine formulation that has been long used in the treatment of cardiovascular diseases, however its mechanisms of cardioprotection remain unclear.We performed murine models of MI in order to model myocardial ischemic damage and examine the effect and underlying mechanism of HXP in protecting against myocardial ischemic injury. We further constructed conditional cardiomyocyte-specific β-catenin knockout mice and induced surgical MI in order to better understand the role of Wnt/β-catenin signaling following myocardial infarction in the adult heart.HXP administration strongly protected against cardiac ischemic injury, improved cardiac function, and markedly decreased the expression of pro-inflammatory cytokines following MI. Nuclear activation of β‑catenin resulted in significantly increased nuclear translocation and activation of NF-κB. In contrast, cardiomyocyte-specific deletion of β-catenin decreased NF-κB activation and exhibited beneficial effects following ischemic injury. Hence, HXP protected against MI-induced ischemic injury and excessive inflammatory response via inhibiting Wnt/β‑catenin signaling.Our study elucidated the role of HXP in protecting against ischemic myocardial injury via preventing MI-induced inflammatory response, which was mediated by its ability to inhibit adverse Wnt/β‑catenin signaling activation. Thus, our study provides the basis for the implementation of HXP as an effective therapeutic strategy in protecting against myocardial ischemic diseases.