Objective To investigate the clinical effect of somatostatin combined with Esomeprazole sodium in the treatment of acute upper gastrointestinal hemorrhage. Methods 98 cases with acute upper gastrointestinal hemorrhage in our hospital from August 2016 to October 2017 were selected as the study objects, they were randomly divided into the control group (somatostatin treatment) and the observation group (somatostatin combined with Esomeprazole sodium treatment), 49 cases in each group. Compare the clinical effect of the two groups. Results After treatment, Blatchford score, hemostasis time and hospital stay of the observation group [(4.88±0.79), (24.51±5.29)h, (9.98±1.99) d] were significantly better than those of the control group [(6.55±0.45), (31.82±5.55)h, (13.24±2.19)d], routine blood indexes and coagulation indexes of the observation group were significantly higher than those of the control group, the difference was statistic significant (P<0.05). Conclusion The application of somatostatin combined with Esomeprazole sodium in the treatment of acute upper gastrointestinal hemorrhage can stop the bleeding in time, reduce inflammation effectively, and improve the clinical effect.