BACKGROUND: Diarrheal disease is a major cause of morbidity and mortality throughout the world, particularly in developing countries. Currently available drugs are linked with adverse effects, contraindications, and risk of resistance. Traditionally, the leaf concoction of Cordia africana is claimed to be used for diarrhea. However, the safety and efficacy of the leaf extract have not been scientifically approved yet. Therefore, the study was conducted to validate its antidiarrheal activity and safety profile in mice. METHOD: The hydromethanolic extract was obtained by the cold maceration technique in 80% methanol. Phytochemical screening tests were done for secondary metabolites by using standard tests. The antidiarrheal activity of the test extract at the doses of 100, 200, and 400 mg/kg was evaluated by using castor oil-induced diarrheal, gastrointestinal transit, and enteropooling models in mice. RESULT: In an acute toxicity study, there were no visible signs of toxicity and mortality following a single oral administration of 2000 mg/kg. Phytochemical screening tests revealed the presence of alkaloids, saponins, flavonoids, terpenoids, phenols, and tannins. The hydromethanolic extract significantly prolonged the onset of diarrhea and reduced the weight of wet and total feces at 100 (P < 0.01), 200 (P < 0.001), and 400 mg/kg (P < 0.001) in the castor oil-induced diarrheal model. However, in the gastrointestinal transit model, a significant (P < 0.001) reduction in the charcoal meal travel was observed in the middle (200 mg/kg) and higher (400 mg/kg) test doses. Similarly, the extract produced a significant (P < 0.001) reduction in the weight and volume of intestinal contents at the aforementioned doses. CONCLUSION: The study demonstrated that the test extract showed promising antidiarrheal activity. Hence, this study supports its antidiarrheal use in Ethiopian folklore medicine.