Objective: To investigate the protective effect of the acacetin on stress gastric ulcer induced by restraint water-immersion stress (RWIS) in mice. Methods: The targets of acacetin and stress gastric ulcer were obtained through the network pharmacology related database, the protein-protein-related action network map was constructed, and the screened intersection targets were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The CB-Dock 2 platform and PyMOL software were used to perform molecular docking and visualization of core targets. In animal experiments, 30 male SPF Kunming mice were randomly divided into the control group, the model group, the acacetin high/low dose group (50/25 mg?kg_-1^{) and} the omeprazole group (20 mg?kg_-1^{) (n=6). A} gastric ulcer mice model was constructed by RWIS (soaking in water at 18°C-20°C for 8 h after restraint), and the gastric ulcer index and pH value of gastric juice were evaluated. Results: The results of network pharmacology showed that there were 54 targets for the intervention of acacetin in stress gastric ulcer. The results of molecular docking showed that acacetin had a strong affinity with the core target proteins epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1) and prostaglandin G synthase 2 (PTGS2). Compared with the model group, the ulcer index of the high and low-dose acacetin groups were significantly reduced (P<0.05). The pH value of gastric juice was significantly increased (P<0.05), and the efficacy was comparable to that of omeprazole group. Conclusion: Acacetin exerts a protective effect on the stomach by inhibiting gastric acid secretion and promoting mucosal repair, which may involve targets such as ESR1, EGFR and PTGS2.