ETHNOPHARMACOLOGICAL RELEVANCE: Searsia dentata and Searsia pyroides are used in traditional South African medicine to treat convulsions and epilepsy. Previous studies have demonstrated that extracts of these plants comprise compounds that bind to the flumazenil-sensitive site on the GABA(A) receptor. However, their use as anticonvulsant medicinal plants cannot be adequately explained by these findings. AIMS: The aim of this study was to examine the possible involvement of the glutamatergic system of extracts from the plants. MATERIALS AND METHODS: The mouse cortical wedge preparation was used for functional characterization of the extracts. The affinity towards the NMDA and the AMPA receptor was investigated using classical [(3)H]-GP39653 and [(3)H]-AMPA binding assays, respectively. RESULTS: The extracts of Searsia dentata and Searsia pyroides inhibited the spontaneous epileptiform discharges in mouse cerebral cortical slices with ED(50) of 0.62 and 1.67mg dry extract/mL, respectively. Both extracts displaced [(3)H]-GP39653 binding and significantly inhibited the NMDA-induced response during co-administration in cortical slices. CONCLUSION: In this study, the NMDA receptor antagonistic effect of the crude ethanolic extracts of these two South African medicinal plants was demonstrated.