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Abstract Objective The amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) is increasingly recognized as a therapeutic target in drug‐refractory pediatric epilepsy. Perampanel (PER) is a non‐competitive AMPAR antagonist, and pre‐clinical studies have shown the AMPAR‐mediated anticonvulsant effects of decanoic acid (DEC), a major medium‐chain fatty acid provided in the medium‐chain triglyceride ketogenic diet. Methods Using brain tissue resected from children with intractable epilepsy, we recorded the effects of PER and DEC in vitro. Results We found resected pediatric epilepsy tissue exhibits spontaneous epileptic activity in vitro, and showed that DEC and PER inhibit this epileptiform activity in local field potential recordings as well as excitatory synaptic transmission. Interpretation This study confirms AMPAR antagonists inhibit epileptiform discharges in brain tissue resected in a wide range of pediatric epilepsies.