Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) as indomethacin has been frequently associated with gastric injury. Honokiol (HK) has demonstrated marked hepatoprotective features; however, its effects on indomethacin-induced gastric injury have not been studied. The aim of the study was to evaluate the potential gastroprotective activity of honokiol against indomethacin evoked gastric mucosal damage. Thirty rats were randomly divided into five groups, 6 animals each, and treated for 21 days: the first group (control group), the second group received honokiol only, the third group received indomethacin, the fourth group received honokiol and indomethacin, the fifth group received Omeprazole and indomethacin. The rat's stomachs were examined in terms of the inflammatory and oxidative perturbations. Results demonstrated that HK attenuated the gross gastric damage, scores of ulcer index, area of mucosal lesions, and histopathology outcomes; actions which were similar to the reference antiulcer drug omeprazole, also pretreatment with HK hampered tumor necrosis factor-α (TNF-α) and significantly decreased Malondialdehyde (MDA) level associated with a significant increase in GSH content, total antioxidant capacity (TAC) level and rise in antioxidants enzyme activities namely; catalase (CAT) and glutathione peroxidase (GPx). In conclusion, the available data in this research proposes that the extracts of Honokiol evidenced to be capable of ameliorating indomethacin-induced gastric ulceration and the possible mechanisms are via anti-oxidative and anti-inflammatory.