A new series of 1-substituted-7-methoxy-5-phenyl-1,2,4-triazolo[4,3-a]quinolines were synthesized using ethyl-3-oxo-3-phenylpropanoate and 4-methoxybenzenamine as the starting material. Their anticonvulsant activity was evaluated by the maximal electroshock (MES) test and 7-methoxy-5-phenyl-1,2,4-triazolo[4,3-a] quinoline (4a) was identified as the most potent compound, with an ED50 value of 9.2 mg kg(-1), which is comparable to the reference drug phenytoin (ED50 = 9.9 mg kg(-1)). To explore the possible mechanism of its anticonvulsant activity, compound 4a was tested with the rotarod neurotoxicity test, pentylenetetrazole (sc-PTZ) test, and isoniazid test. Compound 4a had a higher protective index (PI = TD50/ED50) value (16.6) than phenytoin (PI=7.0), and it antagonized pentylenetetrazole- and isoniazid-induced seizures with an ED50 of 21.1 mg kg(-1) and 83.3 mg kg(-1), respectively.