Indomethacin provokes aggressive ulcerogenic adverse effects. Natural products with fewer side effects are therefore highly requested to attenuate its gastric ulcer effect. Vanillin is a natural compound widely used as flavoring agent which has antioxidant activity. Therefore, the aim of this study was to investigate its gastroprotective effect against indomethacin induced gastric injury. Rats were divided into four groups; first group served as control, group 2: Treated with indomethacin (25 mg/kg, po.), group 3: Pre-treated with ranitidine (reference drug) (50 mg/kg, po., 5 days) before indomethacin and group 4: Pretreated with vanillin (100 mg/kg, po., 5 days). Pre-treatment with vanillin reduced ulcer index, gastric juice volume, free, total acidity and histopathological changes induced by indomethacin. Although it reduced gastric oxidative stress, it elevated enzymatic antioxidant activity and gastric nitric oxide content. Moreover, it reduced gastric NFκB protein expression and activity as well as inhibition in levels of proinflammatory cytokines, Myeloperoxidase (MPO) and caspase 3 activities. It down regulated gene expression of TNF-α, Cytokine-Induced Neutrophil Chemo Attractant (CINC-2α) and caspase-9 while lacking effect on mucosal prostaglandin E2 (PGE2) level. Collectively, vanillin displayed gastroprotective effects in indomethacin induced gastric ulcer by anti-secretory action and cytoprotective effect via antioxidant and anti-inflammatory activities.