Background: The presence of recurrent seizures characterizes epilepsy, which is defined as a chronic disorder of the nervous system. It has recently been suggested that COX-2 inhibitors may offer protective neurotherapeutic effects while simultaneously controlling seizures. The animal model is an important tool for assessing these interventions.

Objectives: This review assessed the literature regarding COX-2 inhibitors in animal models of epilepsy, focusing on their efficacy both in terms of seizure control and neuroprotection. As an effort to inform future research and clinical guidelines, the review collates information on known study gaps, particularly those related to standardized dosing and long-term outcomes.

Methodology: A comprehensive literature search was conducted on Google Scholar, PubMed, Scopus, and Web of Science using the following keywords: “Epilepsy,” “Seizure,” “Neuroprotection,” “Seizure Reduction,” “Inflammatory mediators,” and “COX-2 Inhibitors.” Out of 400 initially reviewed articles, 20 original research articles matched the selection criteria. These studies were conducted in animal models of epilepsy aimed at seizure reduction and neuroprotection through COX-2 inhibitors, and the articles were available in open-access full text. Restricted-access articles, review articles, clinical trials, and those with full-text unpublished data were not included. The risk of bias in the selected studies was assessed with SYRCLE’s tool.

Results: COX-2 inhibitors have been shown to decrease seizures and provide neuroprotection with varying success across many animal models. COX-2 inhibitors showed promise as neuroprotective agents, and their efficacy in seizure reduction has a considerable range. This systematic review highlights the considerable gaps concerning optimized dosage, efficacy duration, and comparative effectiveness across different epilepsy models.

Conclusion: COX-2 inhibitors demonstrated promise in seizure attenuation along with neuroprotection. There are important gaps regarding standardization of treatment protocols, evaluation of chronic impact, and mechanism understanding in different types of epilepsy models, which require focus from further study.