Background: Ischemia heart disease in acute phase has formed Myocardial Infarction (MI) due to imbalance between the vascular supply of oxygen and nutrients and myocardial remands leads necrosis. Objective: Herein, we investigated the cardioprotective effect of plumbagin in isoprenaline hydrochloride (ISO)-induced inflammatory response and increase in antioxidant enzymes and Na+/K+-ATPase activity in MI rats. Materials and Methods: The animals were divided into four groups: Vehicle control group (0.1%), plumbagin group (25 mg/kg/b.w.), ISO group (85 mg/kg/b.w.) injected subcutaneously for 2 days at 24 h interval after a week to induce MI, and plumbagin (25 mg/kg/b.w.) by oral administration for 1 month. The inflammatory and cardiac markers were examined using ELISA kits. The oxidative markers, antioxidant markers, and Na+/K+-ATPase activity was detected using standard methods. Results: According to our results, plumbagin significantly increased the activities of creatine kinase and cardiac troponin T (cTnT). It significantly restored the levels of lipid peroxidation markers (thiobarbituric acid reactive substances [TBARS] and lipid hydroperoxide), increased the antioxidative enzymes (superoxide dismutase, catalase, glutathione [GSH] peroxidase, and the content of GSH), and decreased the levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and nuclear factor kappa B). Histological studies also reveal the decreased inflammatory signs and tissue damages. Conclusion: Our results indicate that plumbagin increased antioxidant enzymes, reduced inflammatory response, and reduced Na+/K+-ATPase activity in rats with MI. Hence, we recommended that plumbagin confers effective cardioprotective activity against ISO-induced MI heart injury.