Leptadenia arborea (Asclepiadaceae) is a plant used in traditional medicine to treat syphilis, migraine, and mental illnesses. The aim of our study was to investigate possible antidepressant and anti-amnesic effects of the aqueous lyophilisate of the leaves of Leptadenia arborea in an animal model of cognitive deficit associated depression. Swiss albino adult mice of both sexes were used for this study. A 14-day combined stress model was used to induce depression with early cognitive deficits. The forced swimming test, the open field test and plasma corticosterone level were used to assess antidepressant-like effect. The novel object recognition task (NORT), the Morris Water Maze (MWM) and neurochemical analysis of hippocampal acetylcholinesterase activity was also carried out to assess memory integrity. The aqueous lyophelisate of L. arborea increased swimming time and decreased immobility time in the forced swimming test. In the open field test they was no difference in the number of lines crossed between groups, and the lyophilisate-treated mice spent more time in the centre compared to the control. The lyophilisate decreased the plasma level of corticosterone compared to the control. The lyophilisate decreased the latency to reach the hidden platform and increased the time spent in the target quadrant in the MWM. The lyophilisate also increased the time of exploration of the novel object in the NORT and decreased the acetylcholinesterase activity in the hippocampus. L. arborea effects were decreased when it was co-administered with pCPA. Results suggest that the aqueous lyophilisate of the leaves of L. arborea possess antidepressant-like and anti-amnesic effects.