Objective To investigate the effect of hydrotalcite combined with esomeprazole on mucosal tissue and microvascular morphology of gastric ulcer. Methods The clinical data of 80 patients with gastric ulcer admitted in the first people′s Hospital of Hefei from January 2016 to January 2017 were analyzed. In the control group, 41 patients received routine therapy (1000mg hydrotalcite, 3 times/d, for 15 days). In the observation group, 39 patients received hydrotalcite combined with esomeprazole (20mg esomeprazole, 2 times/d, for 15d). The clinical efficacy, microvascular morphology, inflammatory factors and collagen deposition area were compared between the two groups. Results The clinical efficacy of the two groups were significantly different (Z=-4.645, P= 0.000). The ratio of round spot pits, short rod pits and no structure in the observation group was lower than that in the control group (P＜0.05). While the ratio of branchlike was higher in the observation group than in the control group (P＜0.05). No difference was found in the ratio of networklike, villous between groups (P＞0.05). The levels of inflammatory rs in the two groups had no significant difference before treatment (P＞0.05) and were significantly decreased at the 10d and 15d. The levels of IL-8, IL-10 and TNF-α in the observation group were significantly lower than those in the control group (P＜0.05). The collagen deposition area between the two groups before treatment had no significant difference (P＞0.05). After treatment, the deposition area of collagen fiber in the observation group was significantly higher than that in the control group (P＜0.05). Conclusion The hydrotalcite combined with esomeprazole can significantly clear the mucosal tissue of gastric ulcer, improve microvascular morphology and reduce inflammatory response.