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Emerging evidence has demonstrated the profound impact of the gut microbiome on cardiovascular diseases through the production of diverse metabolites. Using an animal model of myocardial ischemia–reperfusion (I/R) injury, we found that the prophylactic administration of a well‐known probiotic, Bifidobacterium infantis (B. infantis), exhibited cardioprotective effects in terms of preserving cardiac contractile function and preventing adverse cardiac remodeling following I/R and that these cardioprotective effects were recapitulated by its metabolite inosine. Transcriptomic analysis further revealed that inosine mitigated I/R‐induced cardiac inflammation and cell death. Mechanistic investigations elucidated that inosine suppressed the production of pro‐inflammatory cytokines and reduced the numbers of dendritic cells and natural killer cells, achieved through the activation of the adenosine A2A receptor (A2AR) that when inhibited abrogated the cardioprotective effects of inosine. Additionally, in vitro studies using C2C12 myoblasts revealed that inosine attenuated cell death by serving as an alternative carbon source for adenosine triphosphate (ATP) generation through the purine salvage pathway when subjected to oxygen‐glucose deprivation/reoxygenation that simulated myocardial I/R injury. Likewise, inosine reversed the I/R‐induced decrease in ATP levels in mouse hearts. Taken together, our findings indicate that B. infantis or its metabolite inosine exerts cardioprotective effects against I/R by suppressing cardiac inflammation and attenuating cardiac cell death, suggesting prophylactic therapeutic options for acute ischemic cardiac injury. Highlights: Bifidobacterium infantis, a well‐known probiotic, exhibits prophylactic cardioprotective effects against myocardial I/R injury.The cardioprotective effects of Bifidobacterium infantis are recapitulated by its metabolite inosine.Inosine treatment suppresses cardiac inflammation by reducing the production of pro‐inflammatory cytokines and decreasing the numbers of dendritic cells and natural killer cells after I/R.Inosine treatment attenuates cell death by serving as an alternative carbon source for adenosine triphosphate generation through the purine salvage pathway in stressed myocytes and in I/R‐injured mouse hearts. [ABSTRACT FROM AUTHOR]