Objective: To investigate the ameliorative effect of YiQi KangWei Decoction on gastric mucosal injury in rats with chronic atrophic gastritis (CAG) and to explore its underlying mechanism by which it inhibits pyroptosis of gastric epithelial cells mediated by the NLRP3/Caspase-1/GSDMD signaling pathway. Methods: 39 male SD rats were randomly divided into a control group (n=6) and a model group (n=33), the model group established a CAG model. Among the 30 rats with successful modeling, they were randomly assigned to the CAG model group, the low-dose group of YiQi KangWei decoction, the medium-dose group of YiQi KangWei Decoction, the high-dose group of YiQi KangWei Decoction, and the vitacoenzyme group. Each group consisted of 6 rats. YiQi KangWei Decoction low, medium and high dose groups were intragastric administrated with compound water decoction 5 g/kg/d, 10.15 g/kg/d and 20.3 g/kg/d, respectively, the positive drug group was administered with vitacoenzyme (200 mg/kg/d), the control group and the CAG model group were administered with the same volume of normal saline. The rats were observed for general symptoms during the intervention period, and their body weight was measured weekly. After the intervention, the gastric tissue pathological conditions were observed by HE staining. The levels of serum pepsinogen I (PGI), pepsinogen II (PGII), and the PGI/PGII ratio (PGR) were measured by ELISA, and the levels of interleukin-18 (IL-18) and interleukin-1β (IL-1β) in gastric juice were measured. The expression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), GSDMD-N-terminal fragment (GSDMD-N), and high mobility group box 1 (HMGB1) in gastric tissue was detected by immunohistochemistry. The expression of Caspase-1, cleaved Caspase-1, IL-18, IL-1β, cleaved IL-1β, GSDMD, GSDMD-N, NLRP3, nuclear factor κB (p65), and phosphorylated nuclear factor κB (p-p65) proteins in gastric tissue was measured by Western Blot. Results: Compared with the CAG model group, YiQi KangWei Decoction could improve the mental state and weight gain of rats, improve the histopathological morphology and reduce the pathological scores of gastric tissue, lower the levels of PGI in serum, increase the levels of PGII and PGR, and lower the levels of IL-18 and IL-1β in gastric juice, reduce the expression of NLRP3, GSDMD-N, and HMGB1 in gastric tissue, and lower the expression of cleaved Caspase-1, IL-18, cleaved IL-1β, GSDMD-N, NLRP3, p-p65, and phosphorylated p65 protein. Conclusion: Yi Qi KangWei Decoction may inhibit the occurrence of cell pyroptosis and inflammation in CAG rats by regulating the NLRP3/Caspase-1/GSDMD signaling pathway, thereby alleviating gastric atrophy and gastric tissue damage, providing new theoretical basis and therapeutic ideas for the treatment of CAG.