<p>Drug-resistant epilepsy (DRE) is a substantial medical challenge due to the scarcity of effective therapies. Newly identified mechanisms, such as mitochondrial dysfunction and the Nod-like receptor protein (NLRP3) inflammasome activation, are implicated in playing an important role in the pathogenesis of DRE. Mitochondria are crucial for maintaining neuronal energy balance and cell viability. The NLRP3 inflammasome is triggered when mitochondria are damaged, releasing reactive oxygen species (ROS) and mitochondrial DNA. This activation leads to a cascade of pro-inflammatory reactions, exacerbating neuronal damage and seizures. This review highlights the proposed molecular mechanism involving the interplay of mitochondrial impairment with precipitated NLRP3 inflammasome activation in DRE. It also explores the possibility of implementing drug-delivery techniques to deliver antiseizure medications (ASMs) with agents reversing mitochondrial damage as a novel approach to treat DRE. These advanced delivery methods might improve the efficacy of ASMs, aid in overcoming drug resistance observed in epilepsy, and thus offer a promising means of ameliorating seizure activity in DRE.</p> Graphical Abstract <p></p>