Background <p>Tranexamic acid (TXA) is widely used to reduce blood loss in spine surgery. Different administration routes, including intravenous (IV), topical, and oral, have been studied, but a comprehensive comparison of their efficacy and safety remains lacking. This network meta-analysis aims to compare the effectiveness and safety of various TXA administration methods in spine surgery, focusing on blood loss, transfusion rates and other perioperative parameters.</p> Methods <p>We systematically reviewed randomized controlled trials (RCTs) published until January 2025, comparing different TXA regimens in spine surgery. Data on blood loss, transfusion rates, postoperative complications, post-drainage, length of hospital stay and operative time are extracted. A network meta-analysis is conducted using a Bayesian random effects model to rank the efficacy and safety of TXA routes.</p> Results <p>A total of 12 RCTs involving 1980 patients are included. Topical TXA + IV TXA demonstrated the highest efficacy in reducing intraoperative blood loss, post-operative blood loss, overall blood loss, Hct, Hgb, transfusion rates, post-drainage, operative time and hospital stay, with the highest probability of being the best treatment. Oral TXA showed fewer complications, making it a safer option for low-risk patients. Subgroup analysis confirmed the superiority of topical TXA + IV TXA in spine fusion surgeries, particularly for overall blood loss control and reducing transfusion requirements.</p> Conclusion <p>For open thoracolumbar fusion surgery, Topical TXA + IV TXA is the most effective regimen for reducing blood loss and enhancing recovery in high-risk surgeries. Oral TXA offers a safer alternative for low-risk patients. Extrapolating these findings to other spine procedures still requires further randomized controlled trials. Tailoring TXA administration to individual patient needs optimizes outcomes and reduces complications.</p>