Papaver decaisnei (P. decaisnei) has been used as folkloric medicine for many health issues including gastric problems. The current study investigates the gastroprotective roles of P. decaisnei against ethanol-induced ulcers in rodents. Sprague Dawley rats (30) were separated into five groups: the normal group (G1) and the ulcer control group (G2) were orally administered 0.5% carboxymethylcellulose (CMC); the reference group (G3) was administered 20 mg/kg of Omeprazole; two experimental groups were fed with 200 mg/kg (G4) and 400 mg/kg (G5) of the P. decaisnei extract (PDE), respectively. Next, the rats were given absolute ethanol and sacrificed for the analysis of the gastric mucosal injury through microscopic, enzymatic, histologic, and immunohistochemistry assays. The ulcer controls showed significant superficial hemorrhagic gastric mucosal lesions, with a decreased gastric wall mucus and edema production, whereas fewer were found for the reference and plant-treated rats. Furthermore, the PDE pre-treated rats had a significantly reduced the periodic acid-Schiff (PAS) staining intensity, produced the upregulation of the HSP70 protein, and the downregulation of the Bax protein expressions in the stomach epithelium. P. decaisnei displayed a significant role in the upregulation of endogenous antioxidant enzymes (SOD, CAT, and PGE2), significantly reduced malondialdehyde (MDA), TNF-a, IL-6, and upraised the IL-10 levels. Based on the positive impacts, the PDE can be proposed as the protective/treatment agent against gastric ulcers and stomach lesions.