Myocardial ischemic disease is the major cause of death worldwide. After myocardial infarction, reperfusion of infracted heart has been an important objective of strategies to improve outcomes. However, cardiac ischemia/reperfusion (I/R) is characterized by inflammation, arrhythmias, cardiomyocyte damage, and, at the cellular level, disturbance in Ca2+ and redox homeostasis. In the present study, we sought to determine how acute inflammatory response contributes to reperfusion injury and Ca2+ homeostasis disturbance after acute ischemia. Using a rat model of I/R we show that circulating levels of TNF-α and cardiac caspase-8 activity were increased within 6 hr of reperfusion leading to myocardial nitric oxide and mitochondrial ROS production. At 1 and 15 days after reperfusion, TNF-α-induced caspase-8 activation resulted in S-nitrosylation of the RyR2 and depletion of calstabin2 (FKBP12.6) from the RyR2 complex resulting in diastolic SR Ca2+ leak. Pharmacological inhibition of caspase-8 prior reperfusion with Q-LETD-OPh or prevention of calstabin2 depletion from the RyR2 complex with the Ca2+ channel stabilizer S107 ("Rycal"), inhibited the SR Ca2+ leak, reduced ventricular arrhythmias, infarct size, and left ventricular remodeling after 15 days of reperfusion. TNF-α-induced caspase-8 activation leads to leaky RyR2 channels that contribute to myocardial remodeling after I/R. Early prevention of SR Ca2+ leak trough normalization of RyR2 function represents a new potential therapeutic strategy in cardioprotection.