Recent studies have highlighted the pivotal role of TRPM2 channel activation in neurological disorders. Nevertheless, its association with epileptic seizures and subsequent neuronal damage remains unclear. This study aims to investigate the impact of inhibiting TRPM2 on 4-AP-induced seizures in mouse brain slices and the resultant neuronal damage in the HT-22 cell line. Electrophysiologically using LFP records the effect of TRPM2 inhibition through the TRPM2 antagonist N-ACA was demonstrated in the entorhinal cortex region after the 4-AP-induced seizure model. Furthermore, to shed light on the cellular mechanisms of TRPM2 inhibition regarding post-seizure neuronal damage, the HT-22 mouse hippocampal cell line was employed. Cell viability was assessed through colourimetric assays, while TRPM2 channel expression was demonstrated via immunofluorescence staining. Evaluation of TAS, TOS, and fluorescence ROS levels was conducted using commercial kits, and cytoplasmic calcium levels were determined using Fluo-4 AM. Furthermore, apoptosis was assessed using cleaved caspase-3 immunofluorescence staining and flow cytometry. The inhibition of TRPM2 resulted in a reduction of both the frequency and amplitude of 4-AP-induced seizures in the entorhinal cortex.Moreover, TRPM2 inhibition demonstrated a protective effect against 4-AP-induced neuronal damage by mitigating oxidative stress, reducing calcium influx into cells, and impeding seizures-activated neuronal apoptosis in the HT-22 cell line. In summary, the inhibition of TRPM2 effectively suppressed both 4-AP-induced seizures and neuronal damage by modulating oxidative stress. These findings suggest that TRPM2 could serve as a promising therapeutic target for epilepsy.*The study is funded by TUBITAK with grant numbers 1059B192000306 and 123S164