Objective To investigate the relationship between tissue-specific alterations in brain volume and neurobehavioral status in newborns with complex congenital heart defects preoperatively. Study design Three-dimensional volumetric magnetic resonance imaging was used to calculate tissue-specific brain volumes and a standardized neurobehavioral assessment was performed to assess neurobehavioral status in 35 full-term newborns admitted to the hospital before cardiopulmonary bypass surgery. Multiple linear regression models were performed to evaluate relationships between neurobehavioral status and brain volumes. Results Reduced subcortical gray matter (SCGM) volume and increased cerebrospinal fluid (CSF) volume were associated with poor behavioral state regulation (SCGM, P = .04; CSF, P = .007) and poor visual orienting (CSF, P = .003). In cyanotic newborns, reduced SCGM was associated with higher overall abnormal scores on the assessment ( P = .001) and poor behavioral state regulation ( P = .04), and increased CSF volume was associated with poor behavioral state regulation ( P = .02), and poor visual orienting ( P = .02). Conversely, acyanotic newborns showed associations between reduced cerebellar volume and poor behavioral state regulation ( P = .03). Conclusion Abnormal neurobehavior is associated with impaired volumetric brain growth before open heart surgery in infants with complex congenital heart defects. This study highlights a need for routine preoperative screening and early intervention to improve neurodevelopmental outcomes.