Myocardial infarction (MI) is irreversible damage to the myocardial tissue caused by prolonged ischemia/hypoxia, subsequently leading to loss of contractile function and myocardial damage. However, after a perilous period, ischemia-reperfusion (IR) itself causes the generation of oxygen free radicals, disturbance in cation homeostasis, depletion of cellular energy stores, and activation of innate and adaptive immune responses. The present study employed Abatacept (ABT), which is an anti-inflammatory drug, originally used as an antirheumatic response agent. To investigate the cardioprotective potential of ABT, primarily, the dose was optimized in a chemically induced model of myocardial necrosis. Thereafter, ABT optimized the dose of 5 mg/kg s.c. OD was investigated for its cardioprotective potential in a surgical model of myocardial IR injury, where animals (n = 30) were randomized into five groups: Sham, IR-C, Telmi10 + IR (Telmisartan, 10 mg/kg oral OD), ABT5 + IR, ABT perse. ABT and telmisartan were administered for 21 days. On the 21st day, animals were subjected to LAD coronary artery occlusion for 60 min, followed by reperfusion for 45 min. Further, the cardioprotective potential was assessed through hemodynamic parameters, oxidant-antioxidant biochemical enzymatic parameters, cardiac injury, inflammatory markers, histopathological analysis, TUNEL assay, and immunohistochemical evaluation, followed by immunoblotting to explore signaling pathways. The statistics were performed by one-way analysis of variance, followed by the Tukey comparison post hoc tests. Noteworthy, 21 days of ABT pretreatment amended the hemodynamic and ventricular functions in the rat models of MI. The cardioprotective potential of ABT is accompanied by inhibiting MAP kinase signaling and modulating Nrf-2/HO-1 proteins downstream signaling cascade. Overall, the present work bolsters the previously known anti-inflammatory role of ABT in MI and contributes a mechanistic insight and application of clinically approved drugs in averting the activation of inflammatory response.