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Phytolacca dodecandra (L' Herit), or 'Endod', is one of the widely known medicinal plants in Ethiopia. Berries of the endod have been used as a detergent for centuries. The present study was aimed to test the hepatoprotective effects of the plant against acetaminophen (APAP)-induced liver injury in rats. Mice of either sex were used for oral acute toxicity tests and APAP-induced lethality tests. Hepatoprotective experiments were done on male rats using 2 g/kg of APAP to induce liver damage. Liver enzymes, total bilirubin (TB), and lipid profile were determined. Liver tissues were also examined histopathologically to see a morphologic change in the control and experiment groups. The protective effect of the plant extract was also tested through sodium pentobarbital (SPB)-induced sleeping time. A significant increase in serum levels of liver enzymes, TB, low-density lipoprotein (LDL), and triglycerides (TGs) was seen from oral administration of 2 g/kg APAP. Total cholesterol (TC) and high-density lipoprotein (HDL) levels were decreased. Serum levels of all parameters were reversed to normal after administration of silymarin 100 mg/kg and, 100, 200, and 400 mg/kg doses of the extract. A significant dose-dependent hepatoprotective effect of Phytolacca dodecandra Methanol Root Extract (PDME) was seen in terms of LDL. Histopathological investigations and SPB-induced sleeping time confirmed the findings of biochemical analysis. The findings of the present study indicate that PDME protected the liver from APAP injury., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.