BACKGROUND: The efficacy of postoperative tranexamic acid (TXA) administration in mitigating bleeding after primary laparoscopic Roux-en-Y gastric bypass (RYGB), a prevalent complication associated with significant morbidities and mortality, and the use of sequential laboratory parameter changes in bleeding screening and TXA impact tracking were investigated. METHODS: This retrospective analysis included RYGB patients (aged 18-65 years, with a body mass index of 35-50 kg/m(2)) over 5 years who were categorized into three groups by evolving treatment regimens: Group A (n = 42) received standard pre- and postoperative enoxaparin (30 mg) every 12 h; Group B (n = 160) received enoxaparin and postoperative TXA (250 mg every 6 h); and Group C (n = 73) received TXA alone. Postoperative bleeding-related adverse events, vital signs, and laboratory changes were compared. RESULTS: Postoperative hemorrhage occurred in 3.6% (10/275) of patients, with no significant intergroup differences. Patients who experienced bleeding had greater decreases in hemoglobin (∆Hb) (2.1 vs. 1.4; p = 0.003), greater ∆Hb > 2 (50% vs. 15%; p = 0.013), and greater use of staples than did those who did not experience bleeding (8 vs. 7; p = 0.001). The ∆Hb values were lower in Groups B (1.4) and C (1.3) than in Group A (1.7, p = 0.011). No significant difference was noted between Groups C and B. CONCLUSION: This study emphasizes the potential of TXA to mitigate postoperative bleeding after RYGB, with no added benefit from excluding enoxaparin. Monitoring patients with a ∆Hb > 2 mg/dl and increased stapler usage is crucial. Further research is needed to validate routine TXA use across different procedures.