This prospective, single-center study aimed to evaluate the platelet response during cardiopulmonary bypass (CPB) surgery in a large cohort of children up to 6 years of age. Blood samples were drawn at four time points: after induction of anesthesia, after initiation of the CPB, before protamine, and immediately after chest closure. The study recruited 60 children requiring CPB for surgical repair of congenital heart defects. The platelet count decreased throughout CPB surgery, but during the same period, platelet activity increased. The more pronounced decrease in platelet count observed in children younger than 1 year compared with that of children 1 to 6 years of age was not associated with an age-specific change in platelet activity. The overall increase in platelet function observed in this study could provide a mechanism that compensates for the decrease in platelet count. This study provides a new foundation for future studies investigating requirements of platelet supplementation in the setting of pediatric CPB surgery.