PURPOSE: Neonates undergoing cardiopulmonary bypass (CPB) are at a high risk of a systemic inflammatory response leading to cardiac, respiratory, and renal dysfunction due to their small body size and insufficient adrenal stress response. We hypothesized that corticosteroids reduce systemic inflammatory response and improve clinical outcomes in neonates undergoing cardiac surgery with CPB. METHODS: A systematic search was conducted on six databases including MEDLINE from their inceptions to August 20, 2024. Inclusion criteria were randomized controlled trials (RCTs) comparing corticosteroids and placebo in neonates undergoing cardiac surgery with CPB. The primary outcomes were IL-6 and IL-10 serum levels. The secondary outcomes were postoperative clinical outcomes such as length of intensive care unit (ICU) stay, mortality, and incidence of acute kidney injury. Pooled risk ratios or mean differences (MDs) and 95% confidence intervals (CIs) were calculated using random-effects meta-analysis. Certainty of evidence were assessed following GRADE. This study was registered in PROSPERO (CRD42024548217). RESULTS: Seven RCTs met all inclusion criteria, consisting of 316 patients. Administration of corticosteroids significantly decreased plasma IL-6 on POD1 (MD -64.21 pg/mL, 95% CI -118.26 to -10.16) and plasma IL-10 on POD1 (MD - 4.60 pg/mL, 95% CI - 8.07 to - 1.12). We confirmed corticosteroids administration did not improve clinical outcomes. CONCLUSION: Corticosteroids significantly reduced inflammatory cytokines on POD1. Routine prophylactic use of corticosteroids is not recommended even in neonatal cardiac surgery, however, because of high incidence of adrenal insufficiency in neonates after cardiac surgery with CPB, neonates with clinically suspected adrenal insufficiency could benefit from perioperative corticosteroids administration.