<p>Epilepsy is a debilitating neurological disorder characterized by recurrent seizures and associated with significant cognitive and physical impairments. A variety of factors, including oxidative stress, metabolic imbalances, and genetic mutations, contribute to the etiopathology of epilepsy, and its gradual progression leads to neurodegeneration. Conventional antiepileptic drugs (AEDs) often fail to manage drug resistance in epilepsy, emerging as a hurdle in the current era of research. Overcoming these limitations makes an urge to develop some novel therapeutic strategies. Ral interacting protein 76 (RLIP76), an ATP-dependent transporter, plays a crucial role in maintaining cellular homeostasis by regulating oxidative stress and facilitating the removal of toxic metabolites, such as 4-hydroxynonenal (4-HNE), which are linked to neuronal damage. RLIP76 also modulates like JNK and ERK, influencing cell survival, apoptosis, and drug resistance. Beyond its role in cellular detoxification, RLIP76 is involved in regulating neuronal excitability and synaptic plasticity, which are crucial factors in determining seizure susceptibility. Its multifaceted functions in neuronal stability, protection from oxidative stress-induced damage, and prevention of excessive excitability make RLIP76 an attractive therapeutic target. Modulating RLIP76 activity may induce AEDs’ efficacy by increasing drug availability and reducing multidrug resistance, offering potential for novel therapeutic strategies for epilepsy, especially in drug-resistant cases. This review highlights the structure, functions, and cellular processes of RLIP76, emphasizing its role in epilepsy pathophysiology as a potential biomarker for epileptic conditions and its therapeutic value in the development of targeted therapies, such as small molecule inhibitors and gene therapy, to enhance therapeutic outcomes.</p>