OBJECTIVE : Memantine is a commonly used drug in treating Alzheimer disease. In the current work, we aimed to evaluate the gastro-protective effect of memantine in indomethacin-induced peptic ulcer in rats. METHODS : Peptic ulcer induced by indomethacin and memantine administered either alone or in combination with glibenclamide or nitric oxide synthase (NOS) inhibitor. Ulcer index done and malondialdehyde (MDA), superoxide dismutase (SOD), total nitrites, expression of tumor necrosis factor-α (TNF-α) and expression of nuclear factor kappa B (NF-κB) were measured in gastric mucosa. RESULTS : Memantine reduced ulcer index, reduced MDA, increased SOD, increased total nitrites and reduced expression of both TNF-α and NF-κB. Glibenclamide and not NOS inhibitor abolished the gastroprotective effect of memantine. CONCLUSIONS : Memantine was protective against indomethacin-induced peptic ulcer in rats mostly by affecting potassium channels, antioxidative stress and anti-inflammatory actions.