Combretum duarteanum Cambess. is found in South America, particularly in Bolivia, Paraguay, and Brazil. In Paraiba state (Brazil), the species usually occurs in the Caatinga biome. It is popularly known as mofumbo, cipiúba, or cipaúba. This work aims to evaluate the gastroprotective activity and the cytoprotective mechanisms of the ethanolic extract (Cd-EtOHE) and hexane phase (Cd-HexP) obtained from the leaves of C. duarteanum. Doses at 62.5, 125, 250, and 500 mg/kg of Cd-EtOHE and Cd-HexP were tested in models of gastric ulcers induced by HCl/ethanol, absolute ethanol, stress, non-steroidal anti-inflammatory drugs, and pylorus ligation in male rats or mice. Cd-EtOHE and Cd-HexP significantly reduced gastric injuries induced in all models. Cd-EtOHE and Cd-HexP did not alter gastric juice parameters such as pH, [H(+)], or volume after pylorus ligation. Cytoprotective mechanisms of Cd-EtOHE and Cd-HexP in relation to mucus, nitric oxide (NO), and sulfhydryl (SH) groups were evaluated. Neither product increased the mucus, and they both showed dependence on NO and SH groups to prevent gastric ulcer. Both Cd-EtOHE and Cd-HexP demonstrated gastroprotective activity.