The present study aims to evaluate the gastroprotective potential of riparin III in the acute model of gastric lesions induced by ethanol in mice. Riparin III was synthesized and structurally characterized. Macroscopic evaluations were used through histopathologic tests, in addition to studying the mechanism of action. It also performed biochemical tests, such as nitrite/nitrate levels, reduced glutathione content and malondialdehyde determination. Furthermore, the involvement of iNOS in the gastroprotective effect was evaluated by immunohistochemistry. The results showed the gastroprotective effect of the riparin III, as demonstrated by the reduction of epithelial cell loss, edema, inflammatory infiltrate, and in the number of mast cells. It was also observed that pretreatment with l -NAME and glibenclamide reversed the gastroprotective effect of riparin III, which suggests the participation of ATP-sensitive potassium channels and nitric oxide in the observed effects by the substance under study. Nitrite levels were restored and there was a decreased lipid peroxidation and increased content of reduced glutathione. The immunohistochemical analysis evidenced the participation of iNOS in the gastroprotective effect of riparin III, which corroborated with the nitrite/nitrate dosage and participation of the nitric oxide pathway. Thus, riparin III presented gastroprotective activity and antioxidant potential against ethanol-induced injuries. Graphical Abstract