Hypercapnia has been reported to play an active role in protection against organ injury. The aim of this study was to determine whether a higher level of partial pressure of arterial carbon dioxide (PaCO₂) within the normal range in pediatric patients undergoing cardiac surgery had a similar organ-protective effect. From May 2017 to May 2018, 83 consecutive infant patients undergoing ventricular septal defect (VSD) repair with cardiopulmonary bypass were retrospectively enrolled. We recorded the end-expiratory tidal partial pressure of carbon dioxide (Pet-CO₂) as an indirect and continuous way to reflect the PaCO₂. The patients were divided into a low PaCO₂ group (LPG; 30 mmHg < Pet-CO₂ < 40 mmHg) and a high PaCO₂ group (HPG; 40 mmHg < Pet-CO₂ < 50 mmHg). The regional cerebral oxygen saturation (rScO₂), cerebral blood flow velocity (CBFV), and hemodynamics at five time points throughout the operation, and perioperative data were recorded and analyzed for the two groups. In total, 34 LPG and 49 HPG patients were included. Demographics and perioperative clinical data showed no significant difference between the groups. Compared with LPG, the HPG produced lower postoperative creatine kinase isoenzyme-MB (40.88 versus 50.34 ng/mL, P = 0.038). The postoperative C-reactive protein of HPG trended lower than in LPG (61.09 versus 73.4 mg/L, P = 0.056). The rScO₂ and mean CBFV of HPG were significantly higher compared with LPG (P < 0.05) except at the end of cardiopulmonary bypass. Hemodynamic data showed no significant difference between the groups. As a convenient and safe approach, higher-normal PaCO₂ could attenuate brain injury, heart injury, and inflammatory response in infant patients undergoing VSD repair.