Background <p>Nitric oxide (NO) is reported to play several protective roles in the inflammatory response and ischemia/reperfusion injury. This study evaluated the effect of nitric oxide (NO) on postoperative outcomes in adults undergoing cardiac surgery with cardiopulmonary bypass (CPB).</p> Methods <p>We systematically searched PubMed, Web of Science, and EMBASE (inception–April 2025) for relevant RCTs. Two reviewers independently screened studies, extracted data, and assessed risk of bias (Cochrane RoB 1) and evidence certainty (GRADE). Meta-analysis was performed using random-effects models.</p> Results <p>Eight RCTs involving 774 patients were finally included. The use of NO did not reduce the postoperative mortality (RR 0.71, 95% CI 0.36 to 1.42), the duration of postoperative ventilation (MD -0.23&#xa0;h, 95% CI -1.18 to 0.71), the length of stay in hospital (MD -0.07 days, 95% CI -0.55 to 0.42) or in intensive care unit (MD -4.17&#xa0;h, 95% CI -8.74 to 0.4). This study demonstrated that NO administration significantly reduced serum levels of creatine kinase-MB at both 24&#xa0;h (MD -19.36 ng/ml, 95% CI -28.72 to -10.00) and 48&#xa0;h (MD -17.47 ng/ml, 95% CI -19.53 to -15.41) postoperatively, though it did not affect troponin levels. Concurrently, NO was associated with a significantly lower incidence of postoperative acute kidney injury (RR 0.78, 95% CI 0.64 to 0.93), but not with a reduced need for renal replacement therapy (RR 0.88, 95% CI 0.45 to 1.72).</p> Conclusions <p>This meta-analysis of RCTs did not demonstrate a clear benefit of nitric oxide administered via cardiopulmonary bypass on mortality, duration of mechanical ventilation, or length of stay in adult cardiac surgery. Although suggestive renal and cardioprotective signals were observed, these findings are preliminary and require confirmation in larger, methodologically rigorous trials before definitive conclusions can be drawn.</p> Trial registration <p>INPLASY2022120002.</p>