Background: Significant blood loss is still one of the most frequent issues in spinal surgery. There were different hemostatic methods to prevent blood loss during spinal surgery. However, the optimal hemostatic therapy for spinal surgery is controversial. The purpose of this study was to assess the efficacy and safety of different hemostatic therapies in spinal surgery. Methods: Two independent reviewers conducted electronic literature searches in 3 electronic databases (PubMed, Embase, and Cochrane library database) as well as a manual search to identify eligible clinical studies from inception to Nov 2022. Studies that including different hemostatic therapy (tranexamic acid [TXA], epsilon-acetyl aminocaproic acid [EACA], and aprotinin [AP]) for spinal surgery were included. The Bayesian network meta-analysis was performed with a random effects model. The surface under the cumulative ranking curve (SUCRA) analysis was performed to determine the ranking order. All analyses were performed by R software and Stata software. P value less than .05 was identified as statistically significant. Results: Finally, a total of 34 randomized controlled trials met the inclusion criteria and finally included in this network meta-analysis. The SUCRA shows that TXA ranked first (SUCRA, 88.4%), AP ranked second (SUCRA, 71.6%), EACA ranked third (SUCRA, 39.9%), and placebo ranked the last (SUCRA, 0.3%) as for total blood loss. The SUCRA shows that TXA ranked first (SUCRA, 97.7%), AP ranked second (SUCRA, 55.8%), EACA ranked third (SUCRA, 46.2%), and placebo ranked the last (SUCRA, 0.2%) for need for transfusion. Conclusions: TXA appears optimal in the reduction of perioperative bleeding and blood transfusion during spinal surgery. However, considering the limitations in this study, more large-scale, well-designed randomized controlled trials are needed to confirm these findings.