Cardiac surgery triggers a systemic inflammatory response, especially when cardiopulmonary bypass (CPB) is used, which may contribute to postoperative complications. Ketamine, an NMDA receptor antagonist, has shown anti-inflammatory potential by inhibiting nuclear factor kappa B and reducing cytokine release, but its perioperative immunomodulatory effects remain unclear. This systematic review and meta-analysis assessed randomized controlled trials (RCTs) comparing intraoperative ketamine to placebo in cardiac surgery. The primary outcome was interleukin (IL)-6 level; secondary outcomes included C-reactive protein (CRP) level, intensive care unit (ICU) length of stay, mechanical ventilation duration, and transfusion requirements. Eight RCTs, including a total of 377 patients, were included in the analysis. Ketamine did not significantly reduce IL-6 levels at 24 hours postoperatively (standardized mean difference [SMD], –0.96; 95% confidence interval [CI], –2.56 to 0.65; I² = 96%), although a significant decrease was observed in off-pump procedures (mean difference [MD], –59.57 pg/mL; I² = 0%). IL-6 levels measured immediately after CPB and CRP levels immediately after surgery also were reduced, but findings were limited by high heterogeneity. No significant differences were observed in ICU length of stay (MD, –0.10 days), ventilation time (MD, –0.86 hours), or transfusion rates (risk ratio, 1.01). The certainty of the evidence was rated low to moderate owing to imprecision and inconsistency. Although ketamine’s immunomodulatory effects were observed in selected subgroups, they did not translate into improved clinical outcomes. Current evidence does not support the routine use of ketamine for inflammation control in cardiac surgery, although its effect in off-pump procedures warrants further research.