Intermediate covalent complex of DNA-Topoisomerase II enzyme is a most promising target of the anticancer drugs to induce apoptosis in cancer cells. Currently, Anticancer drug and chemotherapy are facing major challenges i.e., drug resistance, chemical instability and, dose-limiting side effect. Therefore, in this study, natural therapeutic agents (series of Ganoderic acids), were used for the molecular docking simulation against Human DNA-Topoisomerase IIbeta complex (PDB ID:3QX3).Molecular docking studies were performed on a 50 series of ganoderic acids reported in the NCBI-PubChem database and FDA approved anti-cancer drugs, to find out binding energy, an interacting residue at the active site of Human DNA-Topoisomerase IIbeta and compare with the molecular arrangements of interacting residue of etoposide with the Human DNA topoisomerase IIbeta. The Autodock 4.2 were used for the molecular docking and pharmacokinetic and toxicity studies were performed for the analysis of physicochemical properties and to check the toxicity effects. Discovery studio software was used for the visualization and analysis of docked pose.Ganoderic acid GS-1 and Ganoderic acid A were found to be a more suitable competitor inhibitor among the ganoderic acid series with appropriate binding energy, pharmacokinetic profile and no toxicity effects. The interacting residue (Met782, DC-8, DC-11 and, DA-12) shared a chemical resemblance with the interacting residue of etoposide present at the active site of human topoisomerase IIbeta receptor.