Objective The study objective was to expand on prior research examining intraoperative regional cerebral oxygen saturation (rSO2) measured by near-infrared spectroscopy (NIRS) by evaluating the predictive value of perioperative NIRS monitoring for neurodevelopmental outcomes after infant cardiac surgery. Methods Cross-sectional neurodevelopmental evaluation at 24 months of age with the Bayley Scales of Infant and Toddler Development, Third Edition was performed for patients who underwent cardiac surgery with perioperative NIRS monitoring between 2007 and 2010. Retrospective clinical data were extracted from the electronic medical record. Evaluation of selected NIRS measures, including preoperative rSO2 (baseline) as well as rSO2 nadir and percent decrease from baseline during the intraoperative and early postoperative periods, was undertaken. Results Perioperative NIRS and neurodevelopmental data were available for 31 patients without chromosomal anomalies who underwent cardiac surgery during infancy at a median age of 0.43 months. Optimal thresholds on NIRS measures identified through receiver operating characteristic analyses were intraoperative percent decrease of 52% for receptive communication delay and postoperative rSO2 nadir of 56% for cognitive delay and 49% for gross motor delay. When considered in conjunction with other clinical characteristics in stepwise linear regression analyses, intraoperative percent decrease of more than 52% entered into the final model for receptive communication outcome and postoperative rSO2 nadir of less than 56% entered into the final model for cognitive outcome. Conclusions Perioperative NIRS monitoring seems to enhance the ability to predict neurodevelopmental outcome. Specific NIRS measures associated with neurodevelopmental outcome, as well as optimal thresholds, seem to differ across the continuum of the perioperative period.