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Aim The purpose of this research was to investigate the effectiveness and safety associated with various administration routes of tranexamic acid (TXA) in transforaminal lumbar interbody fusion (TLIF) procedures. Methods A cohort of 60 patients who underwent standard TLIF procedures was enrolled and categorized into three groups based on distinct TXA administration strategies: Group A (received preoperative intravenous TXA injection), Group B (received preoperative intravenous TXA injection followed by postoperative oral TXA for 3 days), and Group C (received preoperative intravenous TXA injection followed by postoperative oral TXA for 5 days). Comparative analyses were conducted among the three groups concerning surgical blood loss, operation time, length of hospital stay, hemoglobin and hematocrit levels, coagulation and fibrinolytic markers, transfusion requirements and transfusion rates, incidence of complications, and lumbar spine functionality. Results In comparison to Group A, Groups B and C exhibited reduced total blood loss, concealed blood loss, and postoperative drainage volumes, along with shorter hospital stays. Additionally, Groups B and C demonstrated higher hemoglobin and hematocrit levels, along with lower transfusion rates ( p < 0.05). Notably, no significant disparities were seen between Groups B and C across these observed metrics ( p > 0.05). Furthermore, no substantial differences were identified among the three groups in terms of intraoperative blood loss, drainage tube removal time, coagulation and fibrinolytic markers, complication rates, and JOA and ODI scores one-year post-operation ( p > 0.05). Conclusion Administration protocol involving preoperative intravenous TXA injection followed by 3 days of postoperative oral TXA can effectively decrease total and concealed blood loss, reduce postoperative drainage, shorten hospital stays, elevate hemoglobin and hematocrit levels, and diminish transfusion rates in patients undergoing TLIF surgery. This combined regimen shows a safety profile comparable to preoperative intravenous TXA alone, with no increase in complications or adverse events. Extending oral TXA to 5 days does not provide additional benefit.