Objective To explore the clinical efficacy of somatostatin combined with esomeprazole in the treatment of 98 cases of severe pancreatitis. Methods A total of 98 patients with severe pancreatitis admitted to our hospital from February 2013 to February 2016 were selected for the study. According to the parity of admission order, they were divided into study group and control group, with 49 cases in each group. Control group was given general treatment, and study group was given somatostatin combined with esomeprazole. The changes of serum amylase and C-reactive protein (CRP) were observed before and after treatment. The clinical efficacy and drug safety were compared between the two groups. Results Before treatment, there were no significant differences in serum amylase and CRP concentrations between the two groups (P>0.05). Serum amylase with (126.37±26.51) (U/L) and CRP concentration with (114.26±12.48) (mg/L) in study group after treatment were lower than those in control group with (172.62±25.14) (U/L) and (132.30±15.91) (mg/L). The effective rate of treatment in study group was higher than that of the control group (83.67% vs 57.14%) (P<0.05). There was no significant difference in drug safety between the two groups (P>0.05). Conclusion Somatostatin combined with esomeprazole for severe pancreatitis can improve the clinical efficacy by effectively reducing the pancreas auto digestion and inflammatory reactions, and it has high drug safety, and it is worthy of promotion.