Objective: To explore the combined application value of Bothrops atrox hemocoagulase for injection, somatostatin, and omeprazole sodium in the treatment of acute upper gastrointestinal bleeding (AUGIB). Methods: A total of 80 patients with AUGIB in our hospital from June 2022 to June 2024 were selected as study subjects. The included patients were divided into two groups according to different treatment regimens. All patients received basic treatment. The control group (40 patients) received intravenous drip of omeprazole sodium, while the observation group (40 patients) was treated with intramuscular injection of Bothrops atrox hemocoagulase + intravenous injection of somatostatin + intravenous drip of omeprazole sodium. The improvement of clinical symptoms and coagulation function were observed in both groups, and the clinical efficacy and occurrence of adverse reactions were statistically compared. Results: The comparison of hemostasis time, abdominal pain disappearance time, and melena disappearance time showed that the observation group had shorter times than the control group (P<0.05). The comparison of activated partial thromboplastin time (APTT), prothrombin time (PT), and D-dimer (D-D) after treatment suggested that the observation group was better than the control group (P<0.05). The comparison of total effective rate revealed that the observation group had a higher rate than the control group (P<0.05). No obvious adverse reactions occurred in both groups. Conclusion: In the treatment of AUGIB, the regimen of Bothrops atrox hemocoagulase for injection + somatostatin + omeprazole sodium has a definite therapeutic effect, which can effectively accelerate the improvement of clinical symptoms, promote the recovery of coagulation function, and has good safety.