Gastric ulcer (GU) is a common gastrointestinal disease that can lead to complications such as bleeding, perforation and even cancer. Weiyan I Decoction (WYI) is an effective Chinese medicine prescription against GU. This study aimed to explore the therapeutic mechanism of WYI in GU. WYI constituents were analyzed via ultra-high-performance liquid chromatography-mass spectrometry. SD rats were divided into control, model, lansoprazole (30mg/kg), SB203580 (2mg/kg), WYI (10.8g/kg, 5.4g/kg and 2.7g/kg) groups. GU was induced using ethanol or indomethacin post-WYI pre-administration. Ulcer area, histopathology, serum prostaglandin E2 (PGE2), nitric oxide (NO), gastric tissue cytokines and mitogen-activated protein kinases (MAPKs) were evaluated. Gastric mucus content and pH were determined in the pylorus ligation rat model. Administration of WYI reduced ulcer areas and inflammatory infiltration, elevated serum PGE2 and reduced NO. It decreased gastric tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 levels and inhibited p38 and JNK phosphorylation. The p38 MAPK inhibitor SB203580 significantly reduced the ulcer area, gastric cytokines (TNF-α, IL-1β and IL-6), serum NO and elevating serum PGE2. WYI had no significant impact on gastric acid and mucus secretion. WYI demonstrated gastroprotective effects in GU through anti-inflammatory actions and p38 MAPK pathway inhibition, providing insights for innovative GU therapies.