ABSTRACT Background: Several chemicals and metals, as well as a number of pharmaceutical preparations, are reportedly thought to have a major impact on the emergence of liver disease. According to postcommercialization regulatory considerations, it has been regarded as the most predisposing factor for acute liver failure. Thus, according to recent statistics, nearly 1 in 10 people have a liver illness of some form. 5.5 million of them suffer from chronic liver disease. Any type of viral infection, immune system abnormalities, ingestion of too many poisons, cancer, or other genetic condition may result in liver disease. In addition, the liver may get toxified through some drugs Non-steroidal Anti-inflammatory Drugs (NSAIDs), chemicals, radiation, and ions. Objective: This study involves an in-silico evaluation of one of the soy isoflavones glycitein targeting interleukin-6 (IL-6), IL-1 β, tumor necrosis factor (TNF)-α, and estrogen receptors (ERs) in hepatological disorders by the computational method. The docking result of glycitein is being compared with silymarin as a standard hepatoprotective agent. As a final step, two molecular dynamics (MD) simulation experiments for 150 ns were carried out as a refinement step for the proposed approach. Materials and Methods: The proteins were created using PubChem and viewed by PyMol software. To evaluate the hepatoprotective activity of the selected isoflavone glycitein, selection, and modeling of the target enzymes accompanied by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis using swissADME and pkCSM software was conducted. Furthermore, molecular docking studies using the Auto dock Vina software were carried out to anticipate the binding affinities of Glycitein to the active sites of the intended targets. The proposed method was then refined by the execution of two 150 ns MD simulations and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) studies. Results: All the protein structures were good quality and within the acceptable range. Glycitein exhibited an excellent docking score against IL-6 (−6.4 kcal/mol), IL-1 β (−6.4 kcal/mol), ER (−6.8 kcal/mol), and TNF-α (−6.5 kcal/mol) in comparison with Silymarin which were further screened for drug-likeness and pharmacokinetic parameters including ADMET. Glycitein was found to be the best possible TNF inhibitor hereunder indicated by the MD and MM-PBSA outputs because it demonstrated greater stability and average binding free energy for the ligand-enzyme complex in comparison to Silymarin. Conclusion: The results from the chosen database proved that glycitein is a potent hepatoprotective isoflavone possessing a favorable ADMET profile, lesser or no toxicity, and higher bioavailability which can be further used as a lead compound for preclinical screening.