<p>Drug-resistant epilepsy (DRE) remains a major clinical challenge, with approximately one-third of patients failing to achieve seizure control with standard therapies. Neuroinflammation, oxidative stress, mitochondrial dysfunction, and blood–brain barrier disruption are key drivers of epileptogenesis and pharmacoresistance. Curcumin (CUR), the primary bioactive compound of turmeric (<i>Curcuma longa</i>), exhibits potent anti-inflammatory, antioxidant, and neuroprotective properties relevant to these pathways. However, its clinical translation is severely limited by poor aqueous solubility, low bioavailability, and inadequate brain penetration. Nanoformulation strategies—including solid lipid nanoparticles, polymeric nanoparticles, liposomes, and micelles—have emerged as promising solutions to overcome these pharmacokinetic barriers. Preclinical evidence demonstrates that nano-curcumin (nano-CUR) enhances bioavailability, improves brain delivery, and amplifies therapeutic effects such as seizure suppression, reduction of neuroinflammation, and mitigation of oxidative damage. While early clinical signals are encouraging, significant translational challenges remain, including formulation standardization, safety assessment, and the need for well-designed clinical trials. This review critically evaluates the mechanisms, preclinical evidence, and translational prospects of nano-CUR as a potential adjunctive therapy for drug-resistant epilepsy.</p>