To investigate the feasibility of regional oxygen saturation (rSO₂) monitoring for preventing acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) caused by cardiopulmonary bypass (CPB) in infants undergoing ventricular septal defect (VSD) closure. This study included 49 infants who underwent VSD closure between January 2012 and December 2023. Patients with preoperative pulmonary hypertension were excluded. rSO₂ of the head, abdomen, and thigh was monitored perioperatively. ALI/ARDS was defined as a PaO₂/FiO₂ ratio (P/F ratio) ≤ 300 upon pediatric intensive care unit (PICU) admission. The median age at surgery was 4 (interquartile range: 3–5) months, and the median weight was 6.03 (interquartile range: 5.30–6.78) kg. Five (10%) patients developed postoperative ALI/ARDS and had a longer PICU stay (8 vs 5 days, P < 0.001) and hospital stay (10 vs 5 days, P = 0.005). According to multiple regression analysis, thigh rSO₂ during CPB was a significant predictor of postoperative P/F ratio (β: 4.88, standard error: 1.99, P = 0.02). Receiver operating characteristic curve analysis showed that thigh rSO₂ during CPB (area under the curve: 0.87, P = 0.01) significantly predicted postoperative ALI/ARDS. The optimal cutoff value for thigh rSO₂ was 71%, with a sensitivity of 80% and specificity of 93%. Thigh rSO₂ monitoring during CPB may be effective for detecting ALI/ARDS in infants who underwent VSD closure. Maintaining rSO₂ levels above 71% might help prevent the onset of ALI/ARDS.