Background and Purpose: Oleamide, an endogenous fatty acid amide, had been previously reported to exert various neuromodulatory effects; however, its therapeutic potential in neurological disorders remained unclear. Previously our study demonstrated that oleamide attenuated kainic acid (KA)-induced seizures and excitotoxicity via calpain inhibition. This study aimed to determine whether oleamide exerted neuroprotective and antiseizure effects by inhibiting ferroptosis. Experimental Approach: We investigated the effects of oleamide using HT22 hippocampal neuronal cells and mouse models of epilepsy induced by KA and pentylenetetrazole (PTZ). Mice were administered oleamide either before or after seizure induction to evaluate both prophylactic and therapeutic potential. Molecular and histological analyses were conducted to assess ferroptosis-related markers, oxidative stress levels, and synaptic protein integrity. Key Results: Pre- or post-treatment with oleamide significantly reduced lipid reactive oxygen species (ROS) and restored the expression of key ferroptosis-related proteins, including ACSL4, HO-1, and FTH1. These changes were accompanied by a substantial reduction in seizure severity. Additionally, oleamide preserved synaptic integrity by maintaining the levels of CRMP2, synapsin-1, synaptophysin, and PSD95 in the hippocampus. Moreover, oleamide reversed seizure-induced dysregulation of the mTOR and GSK3β signaling pathways, indicating a multifaceted mechanism of action. Conclusion and Implications: Oleamide exerted both neuroprotective and antiseizure effects in experimental epilepsy models by inhibiting ferroptosis and preserving synaptic function. The results highlighted oleamide as a promising candidate for epilepsy therapy with potential for both prophylactic and therapeutic application.