The present study was conducted to determine the protective effect of Dexmedetomidine (DEX) in myocardial ischemia-reperfusion injury in hyperlipidemic rats. Towards this, the effect of DEX was first evaluated on the infarct size and the histopathology of cardiac tissues using TTC and H and E staining, and it was found that DEX significantly improved the infarct size and architecture of the myocardial tissues following the I/R injury. DEX also showed significant improvement in various examined hemodynamic parameters (e.g., LVSP, and ± dp/dt ) in a dose-dependent manner. The lipid profile (LDL, VLDL, TC, TG, and HDL level) of the rats were also found significantly improved in DEX-treated rats. The level of various pro-inflammatory cytokines (IL-1β, IL-6, IL-10, IL-17, and TNF-α), cardiac injury (CK, CK-MB, Troponin I AST, ALT, and LDH), and oxidative stress (MDA, SOD, and GSH) biomarkers were also found to be restored near to the normal in DEX-treated group. It has been found that DEX also significantly reduces apoptosis of rat cardiomyocytes. In western blot analysis, DEX showed a significant reduction in the activation of NF-κB. In conclusion, our study demonstrated the protective effect of Dexmedetomidine in myocardial ischemia-reperfusion injury in hyperlipidemic rats possibly via amelioration of oxidative stress, and inflammation apoptosis.