With the aim to discover interesting lead compounds that could be further developed into compounds active against pharmacoresistant epilepsies, we first collected 14 medicinal plants used in traditional Chinese medicine (TCM) against epilepsy. Of the six extracts that tested positive in a pentylenetetrazole (PTZ) behavioral zebrafish model, only the ethanol and acetone extracts from Magnolia officinalis (M. officinalis) also showed effective antiseizure activity in the ethylketopentenoate (EKP) zebrafish model. The EKP model is regarded as an interesting discovery platform to find mechanistically novel antiseizure drugs, as it responds poorly to a large number of marketed anti-epileptics. We then demonstrated that magnolol and honokiol, two major constituents of M. officinalis, displayed an effective behavioral and electrophysiological antiseizure activity in both the PTZ and the EKP models. Out of six structural analogues tested, only 4-O-methylhonokiol was active and to a lesser extent tetrahydromagnolo...