〔Abstract〕 Objective To investigate the effects of omeprazole + clarithromycin + amoxicillin on levels of endothelin-1 (ET-1), high mobility group protein B1 (HMGB1), matrix metalloproteinase-9 (MMP-9), extracellular signal-regulated kinase (ERK1/2) and prostaglandin E2 (PGE2) in patients with gastric ulcer. Methods 78 patients with gastric ulcer treated in The People's Hospital of Hebi from January 2021 to December 2022 were selected and divided into an observation group and a control group according to random number table method, with 39 cases in each group. The control group was treated with omeprazole + amoxicillin, and the observation group was treated with omeprazole + clariamycin + amoxicillin. The ulcer healing status, the time for clinical symptoms to disappear, the serum levels of ET-1, HMGB1, MMP-9, ERK1/2 and PGE2 before and after treatment, and the adverse reactions were compared between the two groups. Results The ulcer healing rate of the observation group was 97.44%, higher than 79.49 % of the control group, the difference was statistically significant (P < 0.05). The disappearance time of acid reflux, belching, abdominal distension and abdominal pain in the observation group was shorter than that in the control group, and the difference was statistically significant (P < 0.05). After treatment, the levels of serum ET-1, HMGB1 and MMP-9 in the observation group were lower than those in the control group, and the levels of serum ERK1/2 and PGE2 were higher than those in the control group, with statistical significance (P < 0.05). The total effective rate of the observation group was higher than that of the control group, the difference was statistically significant (P < 0.05). During treatment, there were no obvious adverse reactions in both groups. Conclusion The treatment of gastric ulcer with omeprazole + clarithromycin + amoxicillin can improve the healing rate of ulcer, shorten the time of disappearance of clinical symptoms, and improve the levels of serum ET-1, HMGB1, MMP-9, ERK1/2 and PGE2 without adverse reactions.