Background and Purpose Neuroinflammation is increasingly recognized to contribute to drug-resistant epilepsy. Activation of the ATP-gated P2X7 receptor (P2X7R) has emerged as an important upstream mechanism and increased P2X7R expression is present in the seizure focus in rodent models and patients. Pharmacologic antagonism of the P2X7R can attenuate seizures in rodents but this has not been explored in human neuronal networks. Experimental Approach Human neurons were differentiated from two induced pluripotent stem cell (hiPSC) lines. P2X7R function on neurons was assessed via P2X7R agonist BzATP-evoked calcium transients. Acute or chronic in vitro models of epileptiform-like events were generated by exposure of hiPSC cultures to the GABAA receptor antagonist picrotoxin or a cocktail of picrotoxin and neuroinflammatory agents with or without the presence of P2X7R antagonists. Epileptiform-like activity was measured via single cell patch-clamp recordings. Key Results BzATP application (300 µM) resulted in increased calcium influx in hiPSC-derived neurons which was blocked by the P2X7R antagonists JNJ-47965567 (100 nM) and AFC-5128 (30 nM). Single-cell patch-clamp recordings showed that, while treatment with AFC-5128 did not reduce epileptiform-like activity triggered by picrotoxin alone, AFC-5128 reduced the severity of epileptiform-like activity under inflammatory conditions. Notably, epileptiform-like events in the inflammation-primed picrotoxin model were refractory to the anti-seizure medication carbamazepine alone but were reduced by the co-application of carbamazepine with AFC-5128. Conclusion and Implications Our findings demonstrate anti-seizure effects of targeting the P2X7R in a human neuronal network model of epilepsy and suggest P2X7R-based treatments may be an effective add-on therapy for controlling drug-resistant seizures.