Necrotizing enterocolitis (NEC) is a relatively common complication in neonates with single ventricle physiology following heart surgery. Near-infrared spectroscopy (NIRS) is used to measure regional oxygen saturations in neonates in the postoperative period. We sought to investigate the association of somatic regional oxygen saturation (srSO) and cerebral regional oxygen saturation (crSO) in the early postoperative period and the subsequent development of NEC. We performed a retrospective cohort study of neonates who underwent cardiac surgery with cardiopulmonary bypass from October 2017 to September 2021 at the University of Virginia Children's Hospital. Values of srSO and crSO were captured over the first 48 h following surgery. 166 neonates were included and the median age at time of surgery was 8 days. NEC was diagnosed in 18 neonates following heart surgery with a median interval from surgery to diagnosis of 7 days. Neonates with single ventricle physiology had lower average crSO (62% vs 78%, p < 0.001), average srSO (72% vs 86%, p < 0.001), average crSO to srSO ratio (0.874 vs 0.913, p < 0.001), and an increased average srSO-crSO difference (10% vs 8%, p = 0.03). Adjusting for single ventricle physiology, lower average crSO was associated with the development of definite NEC (modified Bell's criteria stage IIa and higher) (OR = 0.86, 95% CI 0.78-0.96, p = 0.007). Lower crSO values in the early postoperative period in neonates following cardiac surgery was associated with an increased risk in the subsequent development of NEC.