A series of (E)-N0 -(substituted-benzylidene)isonicotinohydrazide derivatives were synthesized by coupling it with different substituted aldehydes, acetophenone, and benzophenones in presence of absolute ethanol along with catalytic amount of glacial acetic acid. All the synthesized compound were confirmed and characterized by using various spectral technique like IR, 1 H NMR, 13C NMR, and mass spectroscopy studies. Anticonvulsant evaluations of all the synthesized compounds were done using various seizures models like maximal electroshock-induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) at a dose of 30, 100, and 300 mg/kg body weight and anticonvulsant activity was noted at 0.5 h and 4 h time intervals after the drug administration. Compound 1a (E)-N0 -2-benzylidene isonicotinohydrazide, 1g (E)-N0 -2-ethoxybenzylidene isonicotinohydrazide, 1k (E)-N0 -3-flourobenzylidene isonicotinohydrazide and 3a (E)-N0 -diphenylmethylene isonicotinohydrazide showed protection in MES model, which indicates that these compounds have the ability to prevent the spread of seizure at 300 mg/kg dose and showed protection at 0.5 h duration. Compound 3a was also found to be active in scPTZ screen at a dose of 300 mg/kg. In neurotoxicity screen, all the synthesized compounds were found non-toxic except compounds 1n, 2a, and 3b. Further compounds 1a, 1g, 1k, and 3a were also evaluated in the minimal clonic seizure model and exhibited potent anticonvulsant activity with lower neurotoxicity. Among all synthesized derivatives, analogue 3a was found to exhibit protection in MES and scPTZ seizure models. This study proved that isonicotinoyl hydrazides synthesized by condensing isoniazid with various aldehydes and ketones displayed moderate to potent anticonvulsant activity.