Objective: Depression is a major neuropsychiatric disorder with a substantial global burden. Existing pharmacotherapies are limited by delayed onset of action, incomplete response, and adverse effects, necessitating the exploration of alternative therapeutic agents, particularly from medicinal plants. Triplochiton scleroxylon was selected based on its ethnomedicinal use and reported richness in bioactive phytochemicals with potential neuropharmacological activity. This study evaluated the antidepressant-like activity, phytochemical composition, and acute toxicity profile of the ethanol leaf extract of T. scleroxylon in murine models.Methods: Fresh leaves of T. scleroxylon were extracted by ethanol maceration, yielding 14.4% crude extract. Preliminary phytochemical screening was conducted using standard qualitative methods. Acute toxicity was assessed using Lorke’s method. Antidepressant-like activity was evaluated in mice (n=4 per group) using the Tail Suspension Test (TST) and Forced Swim Test (FST). Animals received oral doses of 22.5, 45, and 90 mg/kg extract, with imipramine (10 mg/kg) as the reference drug. Results: Phytochemical analysis revealed the presence of flavonoids, alkaloids, tannins, saponins, and steroids. No mortality was observed at 10 and 100 mg/kg in the acute toxicity study, while mortality occurred at 1000 mg/kg. In both TST and FST models, the extract significantly reduced immobility time at 45 and 90 mg/kg in a dose-dependent manner (p