While medicinal plants have garnered significant attention for their potential therapeutic applications in human diseases, the growing reliance on these plants in traditional medicine has raised concerns regarding their safety. This study seeks to evaluate the impact of the ethanol extract of Physalis angulata root on liver marker enzymes as a means of assessing its implications for liver health. Additionally, we present findings on the phytochemical composition and acute toxicity profile of the extract. Phytochemical screening confirmed the presence of alkaloids, glycosides, terpenoids, flavonoids, saponins, reducing sugars, and carbohydrates in the extract. The median lethal dose (LD50) was determined to be 316.23 mg/kg of body weight. Our data revealed statistically significant increases (p≤0.05) in the levels of aspartate amino transferase (AST) and total bilirubin in comparison to the untreated control group. Notably, a significant reduction (p≤0.05) in alanine amino transferase (ALT) levels was observed at a dose of 100 mg/kg body weight of the extract, while higher doses yielded an increase relative to the untreated control. There was also a significant increase (p≤0.05) in the level of total protein in groups treated with 100 mg/kg and 200 mg/kg of the extract, and no significant difference (p≤0.05) in the group treated with 200 mg/kg of the extract relative to the untreated control group. There was no significant difference (p≤0.05) observed in the levels of alkaline phosphatase (ALP) and albumin. In summary, our results indicate that the ethanol extract of Physalis angulata root exhibits dose-dependent toxicity, underscoring the importance of regulating the use of this plant in traditional medicine practices.