Schistosomiasis, caused by flatworm parasites, is a widespread disease resulting in chronic illness and fatalities globally. Given the risk of drug resistance and limited treatment options, finding new therapeutic options are crucial for managing and controlling this neglected tropical disease. In this research, various in-silico methods including Density-Functional-Theory (DFT) computations, Molecular-docking, molecular dynamics simulations and Pharmacokinetic evaluation were employed to identify ten potential inhibitors of Schistosoma mansoni HDAC8 (SmHDAC8). The modeled activities (pIC50) of these newly designed compounds (ranging between 7.110 and 6.959) surpassed that of the hit compound 19 (pIC50 = 6.445) and the standard reference control, Praziquantel (pIC50 = 5.989). Moreover, the MolDock scores (ranging between −188.964 and −158.351 kcal/mol) for these proposed compounds in the SmHDAC8 binding cavity outperformed the hit template 19 (MolDock score: −122.516 kcal/mol) and the Praziquantel (−110.245 kcal/mol). Furthermore, the conformational stability of the top three designed compounds (19a, 19i, and 19j) in the SmHDAC8 binding cavity was examined through a 100 ns of Molecular Dynamics simulation. Additionally, the drug-likeness and ADMET predictions of these compounds indicated favorable oral bioavailability and pharmacokinetic profiles. This study offers a reliable in-silico approach for identifying potential agents against Schistosomiasis.