Marchantia species were traditionally used to treat liver failure. Marchantia polymorpha chloroform extract showed a marked hepatoprotective activity in a dose-dependent manner in paracetamol-induced extensive liver damage in mice. At a dose of 500 mg/kg (MP-500), it resulted in a reduction in aspartate transaminase by 49.44%, alanine transaminase by 44.11%, and alkaline phosphatase by 24.4% with significant elevation in total proteins by 58.69% with respect to the diseased group. It showed significant reductions in total bilirubin, total cholesterol, triglycerides, low density lipoprotein (LDL), very LDL, total lipids, and to high density lipoprotein ratio (CH/HDL) by 53.42, 30.14, 35.02, 45.79, 34.74, 41.45, and 49.52%, respectively, together with a 37.69% increase in HDL with respect to the diseased group. It also showed an elevation of superoxide dismutase by 28.09% and in glutathione peroxidase by 81.83% in addition to the reduction of lipid peroxidation by 17.95% as compared to the paracetamol only treated group. This was further supported by histopathological examination that showed normal liver architecture and a normal sinusoidal gap. Metabolic profiling by ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF/MS) led to the tentative identification of 28 compounds belonging to phenols, quinolones, phenylpropanoid, acylaminosugars, terpenoids, lipids, and fatty acids to which the activity was attributed. Four compounds were detected in the negative ionization mode which are neoacrimarine J, marchantin A, chitobiose, and phellodensin F, while the rest were detected in the positive mode. Thus, it can be concluded that this plant could serve as a valuable choice for the treatment of hepatotoxicity that further consolidated its traditional use.