Cardiopulmonary bypass (CPB) during heart surgery provokes an inflammatory response that can cause post-operative organ injury, yet how CPB shapes key neutrophil effector programs is unclear. We investigated whether CPB differentially regulates neutrophil degranulation versus neutrophil extracellular trap (NET) formation and whether pre-operative neutrophil phenotypes associate with organ dysfunction. In a prospective cohort (n = 39) of children (1 day–4 years) undergoing CPB, blood samples were obtained before CPB and 24 h post-operatively. Purified neutrophils were analyzed for elastase activity and NET formation, alongside phenotypic markers of activation and neutrophil–platelet aggregation. Findings were correlated with acute kidney injury, respiratory failure, and cardiovascular dysfunction. CPB induced marked neutrophilia (4.5-fold rise; p < 0.0001). Elastase release was robustly enhanced after CPB and showed limited augmentation with secondary stimulation but did not predict organ dysfunction. In contrast, NET formation was significantly reduced after CPB. Importantly, diminished pre-operative responsiveness to low-dose NET priming was observed in patients who developed organ injury. Pediatric CPB uncouples neutrophil effector programs, priming degranulation while suppressing NETosis. Pre-operative NET “reserve” may define a clinically relevant innate immune endotype at risk for post-operative organ dysfunction and supports development of biomarker-driven treatment strategies in patients undergoing CPB.