Gastric mucosal injury is caused by an imbalance between the mucosal defense and gastro-irritants, leading to gastroenteritis. Diosgenin is a steroidal sapogenin found in the wild Yam plant that has been reported with several pharmacological properties. The aim of this study is to explore the gastroprotective role of diosgenin on gastric mucosal damage caused by HCl/ethanol in rats. Male Sprague-Dawley rats were intragastrically administered with diosgenin (20 mg/kg) before HCl/ethanol (0.15 M HCl in 98 % ethanol) administration. Omeprazole was used as a positive control. Diosgenin-attenuated oxidative stress by enhancing ( < 0.05) antioxidant enzymes, reducing lipid peroxidation (MDA), and modulating nitric oxide (NO) levels. Anti-inflammatory effects of diosgenin were observed by a reduction in pro-inflammatory cytokines ( < 0.05), decreased myeloperoxidase (MPO) activities ( < 0.05), and histopathological observation of gastric mucosal damage. Western blot analysis provided evidence on the downregulation of NF-κβ by diosgenin. The findings showed that diosgenin has a significant protective role on gastric injury caused by HCl/ethanol, through its antioxidant, anti-inflammatory role, and suppression of NF-κβ and MPO activities.