Perioperative stress detection in children with congenital heart disease (CHD), particularly in the brain, is still limited. Among biomarkers, γ-amino-aminobutyric acid (GABA) assessment in biological fluids appears to be promising for its regulatory action on the cardiovascular and cerebral systems. We aimed to investigate cyanotic (C) or non-cyanotic (N) CHD children for GABA blood level changes in the perioperative period. We conducted an observational study in 68 CHD infants (C: n = 33; N: n = 35) who underwent perioperative clinical, standard laboratory and monitoring parameter recordings and GABA assessment. Blood samples were drawn at five predetermined time-points before, during and after surgery. No significant perioperative differences were observed between groups in clinical and laboratory parameters. In C, perioperative GABA levels were significantly lower than N. Arterial oxygen saturation and blood concentration significantly differed between C and N children and correlated at cardiopulmonary by-pass (CPB) time-point with GABA levels. The present data showing higher hypoxia/hyperoxia-mediated GABA concentrations in C children suggest that they are more prone to perioperative cardiovascular and brain stress/damage. The findings suggest the usefulness of further investigations to detect the “optimal” oxygen concentration target in order to avoid the side effects associated with re-oxygenation during CPB.