This study aimed to compare the release of S100B and NSE between cardiac surgery and interventional therapy for children and to investigate whether S100B serum concentration correlates with cardiopulmonary bypass in children. For this study, 40 children with congenital heart disease were selected and assigned to two groups: group A (20 children undergoing surgical therapy) and group B (20 children undergoing interventional therapy). In group A, blood samples were drawn 10 min after the induction of anesthesia, immediately after aortic cross-clamping, immediately at the end of cardiopulmonary bypass (CPB), immediately at the end of the operation, then 6 and 24 h after the operation. In group B, blood samples were drawn 10 min after the induction of anesthesia, immediately at the end of the procedure, then 6 and 24 h after the procedure. In group A, S100B plasma levels during the perioperative period and 6 h after the operation were higher than the preoperative level (p < 0.05). The NSE plasma concentrations at the termination of CPB and postoperatively were higher than the preoperative level (p < 0.05). Significant correlation was found between the peak value of S100B at the termination of CPB and the durations of both CPB and aortic cross-clamping. In group B, the differences in S100B and NSE between the post- and preoperative levels were not statistically significant (p > 0.05). The perioperative cerebral impairment indirectly evaluated by the release of NSE and S100B protein is greater in children undergoing CPB than in children undergoing interventional therapy. The release of S100B had a strong correlation with the durations of CPB and aortic cross-clamping in children.