Tranexamic acid (TXA) protects against endothelial glycocalyx injury in vitro. We aimed to evaluate whether TXA could protect against endothelial glycocalyx degradation in patients undergoing posterior lumbar fusion surgery. Patients aged 30-80 years were enrolled. The TXA group was administered a loading dose of 10 mg/kg, followed by a 1 mg/kg/h infusion. Serum syndecan-1 and heparan sulfate concentrations, which are biomarkers of glycocalyx degradation, were measured at preoperative baseline (T0), immediately post-surgery (T1), and 2 h post-surgery (T2). Postoperative complications were assessed, including hypotension, desaturation, and acute kidney injury. Among the 121 patients who completed the study, 60 received TXA. There were no significant differences in the marker concentrations at each time point. However, the postoperative increase in syndecan-1 levels from baseline was significantly attenuated in the TXA group compared with the control group (median (interquartile range); T1 vs. T0: -1.6 (-5.3-2.6) vs. 2.2 (-0.7-4.8), p = 0.001; T2 vs. T0: 0.0 (-3.3-5.5) vs. 3.6 (-0.1-9.3), p = 0.013). Postoperative complications were significantly associated with the magnitude of the change in syndecan-1 levels (for T2 vs. T0: odds ratio: 1.08, 95% confidence interval: 1.02-1.14, p = 0.006). TXA administration was associated with reduced syndecan-1 shedding in patients undergoing posterior lumbar fusion surgery.