Epilepsy is a prevalent neurological disorder characterized by recurrent and unprovoked seizures. Despite the availability of anti-epileptic drugs (AEDs), a significant number of patients are still suffering from drug-resistant epilepsy. Neuropeptide Y (NPY) signaling system has emerged as a potential target for the development of anti-epileptic drugs due to its modulation of epileptic activity. In this study, we investigated the therapeutic potential of our previously discovered Scleractinia-derived NPY-like peptide (TpNPY) in seizure disorders. The anticonvulsant effects of TpNPY were evaluated using PTZ-induced seizures in zebrafish and mice in vivo. Furthermore, the underlying molecular mechanisms of TpNPY were assessed using glutamate-induced excitotoxicity models in HT22 mouse hippocampal cells in vitro. Our findings indicated that TpNPY could alleviate PTZ-induced seizure behavior, reduce the expression of seizure-associated immediate-early genes and the production of Reactive Oxygen Species (ROS) in zebrafish. In mice, TpNPY improved seizure behaviors, decreased inflammatory cytokine levels, and ameliorated abnormal glial activation in a PTZ kindling epileptic model. Besides, the administration of TpNPY could attenuate the PTZ-induced anxiety levels and improve recognition memory deficits. Moreover, TpNPY promotes neurogenesis and neural synaptic plasticity through the BDNF/TrkB signaling pathway. Additionally, TpNPY restored cell injury and attenuated oxidative stress in glutamate-challenged HT22 cells through the Nrf2/HO-1 signaling pathway. These results highlight the potential therapeutic efficacy of TpNPY in the treatment of seizures and provide new insights into the development of coral-derived anti-epileptic peptide-based drugs.