Background. Activation of the adenosine receptor (R) can reduce myocardial ischemia/reperfusion (IR) injury. However, the mechanism underlying the R-mediated cardioprotection is less clear. The present study was designed to investigate the potential mechanisms of cardioprotection mediated by R. Methods and Results. C57BL/6 mice underwent 40-minute ischemia and 60-minute reperfusion. ATL-801, a potent selective R antagonist, could not block ischemic preconditioning induced protection. BAY 60-6583, a highly selective R agonist, significantly reduced myocardial infarct size, and its protective effect could be blocked by either ATL-801 or wortmannin. BAY 60-6583 increased phosphorylated Akt (p-Akt) levels in the heart at 10 min of reperfusion, and this phosphorylation could also be blocked by ATL-801 or wortmannin. Furthermore, BAY 60-6583 significantly increased M2 macrophages and decreased M1 macrophage and neutrophils infiltration in reperfused hearts, which also could be blocked by wortmannin. Meanwhile, confocal imaging studies showed that the majority of Akt phosphorylation in the heart was colocalized to CD206+ cells in both control and BAY 60-6583 pretreated hearts. Conclusion. Our results indicated that pretreatment with BAY 60-6583 protects the heart against myocardial IR injury by its anti-inflammatory effects, probably by modulating macrophages phenotype switching via a PI3K/Akt pathway.