Hepatocellular carcinoma is the most common cause of death, having 75% of all primary liver malignancies worldwide. Luminespib (heat shock protein inhibitor) was found efficiently active against various tumours and hence acted as a key to the research. In this research isoxazole-piperazine derivatives were subjected to QSAR, molecular docking, and MD simulations studies. The QSAR results indicated the importance of First order molecular connectivity index (1χ; r= 0.775, q2 = 0.532) for MCF-7 cell line; Second-order molecular connectivity index (2χ; r = 0.880, q2 = 0.730) for Huh -7 cell line; Lowest unoccupied molecular orbital and Randic topological index (LUMO, R; r = 0.703 and q2 = 0.347) for Mahlavu cell line in describing the anticancer activity of isoxazole-piperazine derivatives. The significance of constructed models has been supported by statistical parameters. Further, molecular docking was done to understand the molecular interactions with the target protein human topoisomerase II (PDB ID: 3QX3), which predicted the anticancer activity against MCF-7, Huh-7 and Mahlavu cell lines. The docking results demonstrated that compounds 15, 7m, and 7f showed best docking score along with binding with crucial amino acid residues. Further, MD simulation was done for compounds 13c and 13d depending on their biological activities, docking score and molecular interactions with the target. The results of MD simulations showed stability of the compounds. Finally, these compounds may be used as a new lead for further discovery.