Background: Gastritis, a prevalent global malady, stems from various factors such as unhealthy lifestyles, bacterial infections, or non-steroidal anti-inflammatory drug usage. If untreated, it leads to severe complications. Hedyotis capitellata Wall., recognized for its medicinal properties, is traditionally acknowledged for its effectiveness in pain relief, neutralizing gastric acid, reducing acid reflux, and promoting ulcer healing. The aim of the study:This study delves into exploring the preventive and protective prowess of H. capitellata leaf ethanol extract (EEHC) against indomethacin (IND)-induced gastric mucosal damage in mice. Materials and methods: EEHC administered at 300, 350, and 400 mg/kg doses, with omeprazole (OME) (20 mg/kg) as the reference standard, EEHC's impact was assessed on gastric acid levels, mucosal damage, malondialdehyde (MDA) content, antioxidant activity (catalase, myeloperoxidase, glutathione, total antioxidant capacity), cytokine levels (TNF-α, IL-1β, IL-6, IL-10), and histopathology. Results: EEHC, particularly at 400 mg/kg, exhibited maximal inhibition of total gastric acid (8.58 ± 0.16 mEq/l), decreased MDA content (5.29±0.15 nM/g tissue), and lowered pro-inflammatory cytokines (TNF-α: 224.04±17.56 pg/ml) compared to IND-treated mice (p<0.05). Dose-dependent EEHC enhanced the antioxidant defense system by reducing catalase and myeloperoxidase activity and increasing glutathione and total antioxidant capacity levels (p<0.05). Mice treated with EEHC displayed significantly lower gastric ulcer indices across all experimental models compared to the IND-treated group (p<0.05). Histopathological examinations further affirmed EEHC's anti-inflammatory efficacy. Conclusion: The study establishes that oral administration of EEHC exerts a positive protective influence on the gastric mucosa, augmenting the antioxidant defense system and anti-inflammatory effects. H. capitellata emerges as a promising resource for managing gastric inflammation due to its potent antioxidant properties