Objective To explore the effects of omeprazole and esomeprazole on the efficacy and safety of upper gastrointestinal bleeding. Methods 96 patients with upper gastrointestinal bleeding were divided into omeprazole group (group A, n=48) and esomeprazole group (group B, n=48) according to the random number table method. Group A was given routine treatment + intravenous infusion of omeprazole, and group B was given conventional treatment + intravenous infusion of esomeprazole. The efficacy and adverse reactions of the two groups were compared. The changes of packed cell volume (PCV) and serum urea nitrogen (BUN) were observed before and after treatment. Results There was no significant difference in the total effective rate of treatment between the two groups (P>0.05). After 5 d of treatment, the PCV in the two groups was higher than that before treatment, and the serum BUN was lower than that before treatment (P<0.05), and the difference was not statistically significant between-groups (P>0.05). The incidence rate of adverse reactions in group A was higher than that in group B (25.00% vs 8.33%) (P<0.05). Conclusion Omeprazole and esomeprazole both have high efficacy in the treatment of upper gastrointestinal bleeding, and there is no significant difference, but esomeprazole has fewer adverse reactions and higher safety.