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Medicinal plants have long served as sources of therapeutic agents for various human ailments. However, their complex chemical compositions may also present toxic effects, underscoring the need for scientific evaluation to ensure safety. Rhodognaphalon brevicuspe, traditionally used in the treatment of arthritis and certain venereal diseases, has not been scientifically assessed for its toxicity. This study evaluated the acute oral toxicity of the crude ethanolic extract of R. brevicuspe. Plant material was extracted with ethanol, and column chromatography combined with repeated recrystallization yielded four isolates: RB01, RB02, RB03 and RB04. Acute oral toxicity testing of the crude extract was performed in rats according to OECD guideline 423. Over a 14‑day observation period, no mortality or significant signs of toxicity were recorded. Clinical biochemistry of blood samples after 14days of treatment with extract showed no significant differences between control and extract treatment groups for liver and kidney biomarkers. The extract’s approximate median lethal dose (LD50) was > 2000mg/kg. These findings suggest that the crude extract of R. brevicuspe is relatively safe under the conditions tested, supporting its continued investigation as a potential source of therapeutic agents.