In this study, novel substituted 2-(5-(2-phenylquinolin-4-lyl)-1,3,4-oxadiazol-2-ylthio)-1-(4-phenylpiperazine-1-yl) ethanones (11a-i) were synthesized and assessed for their anticonvulsant potential. The structures of the synthesized compounds were confirmed through FT-IR, H NMR, C NMR, and mass spectrometry. In vivo, anticonvulsant investigations were performed using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPTZ) induced epilepsy animal models. Compounds 11b, 11e, and 11 h demonstrated the most promising action against the induced seizures. To prove that the synthetic derivatives' ability to prevent seizures is not caused by any depression brought on by the use of synthesized derivatives, antidepressant activity has been conducted via a forced swim test (FST). In addition, in silico evaluations comprising ADME predictions, molecular docking, and molecular dynamics simulations on GABA receptors were also performed to determine the pharmacokinetic profiles, binding mode, orientation, and stability of synthesized compounds at the active sites of the targets. The electronic structure of synthesized compounds was also described by density functional theory (DFT) through various reactivity descriptors such as HOMO, LUMO, electron affinity, ionization potential, chemical potential, and global softness. The results of computational studies reinforced the findings of in vivo screening. In summary, this study introduces a promising class of piperazine-1,3,4-oxadiazole-quinoline hybrids with significant antiepileptic properties, warranting further pharmacological exploration for their potential clinical applications.