Background: Cardiopulmonary bypass (CPB) may lead to tissue hypoxia, inflammatory response, and risk for acute kidney injury (AKI). We evaluated the prevalence of AKI and inflammatory response in neonates undergoing heart surgery requiring CPB with or without antegrade cerebral perfusion (ACP). Methods: Forty neonates were enrolled. The patients were divided into two groups depending on the use of ACP. AKI was classified based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Inflammatory response was measured using plasma concentrations of interleukins 6 (IL-6) and 10 (IL-10), white blood cell count (WBC), and C-reactive protein (CRP). Results: Eight patients (20%) experienced AKI: five (29%) in the ACP group and three (13%) in the non-ACP group (P = 0.25). Postoperative peak plasma creatinine and urine neutrophil gelatinase-associated lipocalin were significantly higher in the ACP group than in the non-ACP group [46.0 (35.0–60.5) vs 37.5 (33.0-42.5), P = 0.044 and 118.0 (55.4–223.7) vs 29.8 (8.1–109.2), P = 0.02, respectively]. Four patients in the ACP group and one in the non-ACP group required peritoneal dialysis (P = 0.003). Postoperative plasma IL-6, IL-10, and CRP increased significantly in both groups. There were no significant differences between the ACP and non-ACP groups in any of the inflammatory parameters measured. Conclusions: No significant difference in the AKI occurrence or inflammatory response related to CPB modality could be found. In our study population, inflammation was not the key factor leading to AKI. Due to the limited number of patients, these findings should be interpreted with caution.