ETHNOPHARMACOLOGICAL RELEVANCE: Helicteres sacarolha A. St.- Hil. et al. popularly known in Brazil as 'semente-de-macaco', is widely employed in the popular medicine in many of parts of Brazil in the alleviation of symptoms of ailments such as peptic ulcer and inflammation. Up to the present, there is no study addressing the gastroprotective activity of the hydroethanolic extract of H. sacarolha and its possible mechanism of actions. MATERIALS AND METHODS: The hydroethanolic (70%) extract of H. sacarolha (HEHs) was obtained by maceration. The gastroprotective activity was assessed using gastric ulcer models induced by acidified ethanol, piroxicam, and water restraint stress in mice and rats at doses of 20, 50 and 250mg/kg p.o. Mechanistic studies involved the antisecretory assay evaluated with pylorus ligation in rats and pre-treatments with appropriate antagonists/inhibitors such as yohimbine, glibenclamide, indomethacin and l-NAME, effect on catalase and myeloperoxidase activities and gastric mucus determination using acidified ethanol- induced ulcer in mice. RESULTS: HEHs at all doses tested demonstrated potent gastroprotective activities in the acute ulcer models. The gastroprotective activity of HEHs was attenuated by pre-treatments with yohimbine, glibenclamide, indomethacin and l-NAME. HEHs effectively reduced basal gastric juice production without any effect on the free and total acidity. The gastroprotective action of HEHs involved increasing the antioxidant enzyme catalase and mucus secretion and inhibition of neutrophyl infiltration as reflected by the reduction in the myeloperoxidase activity. CONCLUSION: The results of this study gave a scientific support for the popular use of the leaves of H. sacarolha in the treatment of gastric ulcers and that it has a multi-targeted action.