Abstract: Objective To explore the efficacy of rebamipide combined with esomeprazole in the treatment of erosive gastritis and its influence on the mucosal barrier. Methods 96 cases of erosive gastritis admitted to Ningguo People's Hospital from February 2024 to February 2025 were selected, and randomly divided into the observation group and the control group, with 48 cases in each group. The control group received esomeprazole on the basis of conventional treatment, while the observation group was additionally treated with rebamipide tablets on the basis of the control group regimen. All patients were treated continuously for 4 weeks. Clinical efficacy at 4 weeks after treatment was compared between the two groups. Gastric mucosal barrier function indicators pepsinogen (PG) Ⅰ, PG Ⅱ, PG Ⅰ/PG Ⅱ ratio, gastrointestinal hormones gastrin (GAS), motilin (MTL), and gastric mucosal morphology scores (mucosal thickness, inflammatory cell infiltration) were compared at baseline, 2 and 4 weeks after treatment. Gastrointestinal Quality of Life Index (GIQLI) scores were also compared at baseline, 4 weeks after treatment and the 1-month follow-up. Adverse reactions during treatment were recorded. Results After 4 weeks of treatment, the observation group had a significantly higher overall response rate compared with the control group (P < 0.05). At 2 and 4 weeks post-treatment, the observation group presented higher levels of PG I, PG I/PG II ratio and MTL, as well as lower GAS level, mucosal thickness score and inflammatory cell infiltration score (P < 0.05). Significantly higher GIQLI scores were also observed in the observation group at 4 weeks after treatment and the 1-month follow-up (P < 0.05). No significant difference in adverse reactions was found between the two groups (P > 0.05). Conclusion Rebamipide combined with esomeprazole achieves remarkable efficacy in the treatment of erosive gastritis. It can effectively improve gastric mucosal barrier function, gastrointestinal hormone levels and gastric mucosal morphology, with a favorable safety profile. This regimen is worthy of clinical application.