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Ximenia americana L., popularly known in Brazil as “ameixa do-mato, ameixa-brava, and ameixa-do-sertão,” is widely used in folk medicine to treat several intestinal disorders. The present study assessed the potential mechanisms of action underlying the gastroprotective activity of the hydroethanolic extract of Ximenia americana L. (EHXA) stem bark. The acute toxicity of EHXA was estimated, and later, the gastroprotective effect in mice was assessed through acute models of gastric lesions induced by acidified or absolute ethanol and indomethacin, where the following mechanisms were pharmacologically analyzed: the involvement of prostaglandins (PG), histamine (H2) receptors, ATP-dependent potassium channels, sulfhydryl groups (SH), α2 adrenergic receptors, nitric oxide (NO), myeloperoxidase (MPO), gastric mucus production, and acetylcholine-mediated intestinal motility. Regarding toxicity, EHXA did not cause deaths or signs of toxicity (LD50 greater than or equal to 2000 mg/kg/p.o.). When the gastroprotective effect was assessed, EHXA (50, 100, and 200 mg/kg/p.o.) reduced the rate of lesions induced by acidified ethanol by 65.63; 53.66, and 58.02% in absolute ethanol at 88.91, 78.82, and 74.68%, respectively, when compared to the negative control group. In the indomethacin-induced gastric injury model, the reductions were 84.69, 55.99, 55.99, and 42.50%, respectively. The study revealed that EHXA might stimulate mucus production and reduce intestinal motility through SH groups, NO production, and activation of α2 adrenergic receptors. The results indicated that EHXA had significant gastroprotective activity in the evaluated models. However, further investigation is required to elucidate the cellular and molecular events underlying the action of EHXA components and to correlate them with the modulation of the signaling pathways, as demonstrated by the current pharmacological approach. Therefore, the results demonstrated in the present study, as well as previously reported findings, support the recommendation of using this species in traditional communities in Brazil.