A series of 5,6-dimethoxy-2-{1-[arylamino/ alkylamino(thioxo)methyl]-4-piperidyl-methyl}-1-indanones (4a–l) were designed and synthesized by the reaction of 5,6 dimethoxy-2-(piperidin-4-yl-methyl)-indan-1-one with aryl/ alkyl isothiocyanates. The anticonvulsant activity was evaluated in animal models by maximal electroshock seizure and subcutaneous pentylenetetrazole tests. The neurotoxic effects were assessed by rotorod and ethanol potentiation tests. Gamma amino butyric acid (GABA) estimation of the selected compounds was performed in rat brain utilizing UV absorbance data. Compounds 4d, 4g, and 4j displayed encouraging anticonvulsant profile against both seizure models with remarkably lower neurotoxicity. These compounds were found to increase the GABA level in rat brain significantly.