Long non-coding RNAs (lncRNAs) play significant roles in neurological diseases, including epilepsy. Our previous study identified lncRNA-GPHN as specifically downregulated in a rat model of status epilepticus (SE). Investigate the role and regulatory mechanism of lncRNA-GPHN in the pathogenesis of epilepsy. SE rat and in vitro cell models were used to analyse expression dynamics, cellular localisation, and effects of lncRNA-GPHN on epileptic seizures, followed by HE staining, Nissl staining, and TUNEL staining. Luciferase Reporter assay, ChIRP assay, real-time quantitative PCR, and Western blotting accompanied with TUNEL assay and whole-cell patch-clamp techniques were employed to determine the molecular mechanism in lncRNA-GPHN regulating epilepsy in neurons. Post-seizure, lncRNA-GPHN in SE rats' hippocampus was markedly downregulated, hitting a nadir at 24 h. FISH and qPCR confirmed its cytoplasmic localization in neurons. EEG showed that lncRNA-GPHN overexpression significantly curtailed seizure frequency and intensity, elevating the threshold, while MWM results pointed to enhanced cognition in SE rats. Histological staining revealed less neuronal damage and better cellular integrity in overexpressing rats, accompanied with a reduction in neuronal apoptosis. In vitro, lncRNA-GPHN reduced neuronal excitability and epileptic potentials dose-dependently. q-PCR and ChIRP showed lncRNA-GPHN upregulates YWHAH by sequestering miR-320. Dual-luciferase and Western blot validated miR-320's direct suppression of YWHAH and lncRNA-GPHN's counteracting effect. TUNEL staining confirmed that miR-320 overexpression increased apoptosis, mitigated by lncRNA-GPHN overexpression and further reduced with combined overexpression. lncRNA-GPHN ameliorates epilepsy by inhibiting apoptosis via the miR-320/YWHAH axis, providing insights into epilepsy pathogenesis and potential targeted therapeutic strategies.