Milicia excelsa (Moraceae) leaf is used as tonic and anti-stress agents to reinvigorate the body among other ethnomedicinal claims in African traditional medicines, but there is lack of scientific data on its efficacy. Hence, this study investigated the anti-stress potentials of the ethanol leaf extract of Milicia excelsa on anxiety-, and depressive-like behaviours induced by acute restraint stress in mice. The effect of the extract on spontaneous locomotor activities of mice was also evaluated. The extract at all the doses of 50, 100 and 200 mg/kg, p.o. significantly (p<0.05) increased the percentage open arm entries and percentage open arm duration as well as demonstrated anti-anxiety effect as shown by the open arm avoidance index on elevated plus maze. The extract also significantly (p<0.05) reduced immobility time of mice in tail suspension test, indicating antidepressive-like effect. Subsequently, the extract at all the doses used in this study did not modify the spontaneous locomotor effect of the experimental mice suggesting that the observed anti-stress effect was neither due to stimulation nor sedation. This study, therefore, concluded that the extract may possess specific anti-stress effect, effective against anxiety and depression induced by acute restraint stress, thus providing scientific evidence for its suggested ethnomedicinal usage.