<p>Pediatric cardiac surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest is associated with global myocardial ischemia-reperfusion (IR) injury, leukocyte activation, and a systemic inflammatory response that contributes to early postoperative morbidity and mortality. The mechanisms for acute myocardial dysfunction and end-organ injury after pediatric heart surgery are complex and incompletely understood. This study aimed to: (1) investigate the contributions of the toll-like receptor-4 (TLR-4) pro-inflammatory and the pro-survival hypoxia-inducible factor-1α/phosphatidylinositol 3-kinase (HIF-1α/PI3K) pathways to global myocardial IR injury and inflammation, and (2) evaluate the impact of nicorandil, a coronary vasodilator and anti-ischemic agent, on TLR-4 and HIF-1α/PI3K signaling and end-organ dysfunction in a neonatal piglet model of CPB and cardioplegic arrest.&#xa0;Piglets (4–5 weeks old, <i>N</i> = 12) were randomly assigned to IR or IR + nicorandil. After initiation of CPB with cardioplegic arrest, hearts were reperfused on partial CPB, followed by complete separation from CPB. Left ventricular (LV) systolic and diastolic pressures were continuously recorded, and serial blood and terminal tissue samples were collected to measure inflammation, oxidant stress (OS), and apoptosis.&#xa0;CPB with cardioplegic arrest transiently and significantly impaired both LV contractility (<i>p</i> = 0.01) and diastolic relaxation (<i>p</i> = 0.001) associated with a 39-fold increase in cardiac TLR-4 expression (<i>p</i> = 0.034), a 3-fold increase in IL-6 production (<i>p</i> = 0.01), and significant increases in plasma markers for end-organ injury, but without the expected upregulation in the HIF-1α/PI3K pro-survival pathway. Nicorandil pre-treatment significantly augmented LV systolic (<i>p</i> = 0.004) and diastolic (<i>p</i> = 0.002) functional recovery associated with attenuated upregulation of TLR-4 signaling pathways, augmented HIF-1α/PI3K pro-survival signaling, and reduced inflammation, OS, apoptosis, and end-organ injury.&#xa0;Our piglet model of CPB with cardioplegic arrest demonstrates that the TLR-4 pro-inflammatory signaling pathway plays an essential role in myocardial IR-induced cardiac dysfunction, inflammation, OS, apoptosis, and multi-organ injury. Nicorandil pre-treatment attenuates these effects. Nicorandil also upregulates the HIF-1α/PI3K pro-survival signaling pathway. These results suggest that nicorandil should be studied further to assess its potential therapeutic effects after CPB in children.</p>