INTRODUCTION: Lysine analog antifibrinolytics (LAAF) like tranexamic acid (TXA) and aminocaproic acid (EACA) reduce intraoperative blood loss, especially in cardiac surgery where bleeding risks are high. These LAAF inhibit fibrinolysis and have been proven to decrease bleeding and transfusion volume. In cardiac surgery, frequent transfusions raise the risk of infections, extend hospital stays and reoperations, and carry higher morbidity and mortality. While intravenous administration is well-supported, topical LAAF application may further enhance hemostasis and improve outcomes, though evidence for topical use is less robust. METHODS: Pubmed, Embase, MEDLINE, Cochrane CENTRAL, and Clarivate WoS were searched from inception to August 31st, 2024, for randomized controlled trials and observational studies comparing topical TXA or EACA to placebo in cardiac surgery. Data extraction was done independently, and RoB2/ROBINS-I was used for quality assessment. A derSimmonian-Laird random-effects model was applied. Mean differences were used for continuous outcomes, and OR/RR was used for binary. I2 statistics measured heterogeneity. Sensitivity analysis and GOSH plotting assessed heterogeneity; trial sequential analysis was performed. Certainty of evidence followed GRADE guidelines. RESULTS: The meta-analysis included 26 studies with 2,624 patients, 24 focused on adults. Given the pragmatic approach for this meta-analysis, a wide variety of surgical procedures were included, with coronary artery bypass grafting (CABG) and valvular procedures being the most prevalent. LAAF administration reduced postoperative blood loss by 174 ml (MD -173.99, CI95 -238.20 to -109.78, p <0.00001), the effect remained constant through subgroup analysis (CABG, High vs Low-dose, Dual-route administration). No significant differences were found in transfusion rates for packed red blood cells (PRBC) and platelets, though LAAF reduced PRBC volume (MD -0.6 units, CI95 -0.88 to -0.24 p = 0.00006) and fresh frozen plasma (FFP) requirements (RR 0.69, CI95: 0.5 to 0.95, p = 0.03). No differences in hematological change scores and complication rates were observed. The analysis showed high heterogeneity, but the overall effect remained consistent. A trial sequential analysis suggests there is enough data to confirm this effect. CONCLUSION: Topical LAAF administration reduces postoperative blood loss up to 24 hours postoperatively, lessening PRBC transfusion volume and FFP transfusion rate without increasing complications. Registration: PROSPERO CRD42024579777, August 27th, 2024