Epilepsy is the second most common chronic central nervous system disorder. Oxcarbazepine (OXC) is an antiepileptic drug with low solubility in aqueous media but is used for the treatment of both focal and generalized seizures. Studies of OXC encapsulation in nanostructured lipid carriers (NLCs) composed of cetyl palmitate and oleic acid coated with polyvinyl alcohol (PVA) or chitosan (Ch) to obtain nanoparticles with negative and positive surface charge, respectively, are reported. All NLCs displayed 97%–98% OXC encapsulation efficiency, 14.5%–14.6% drug loading, 121.8–212.3 nm size range, and polydispersity indexes between 0.248 and 0.282 nm, depending on their composition. The homogeneity of the NLCs was confirmed by electron microscopy. The OXC release from the NLCs was analyzed by Higuchi, Baker-Londsdale, and Korsmeyer-Peppas structured models. The Korsmeyer-Peppas model provides the best data fit (R2 > 0.98), and n > 0.58, suggesting a mechanism driven by non-Fickian molecular release. In vitro permeability studies using MDCK-MDR1 cells revealed enhanced permeability of the encapsulated drug compared with free OXC. Surface plasmon resonance tested in the presence of BSA, IgG, and IgM, commonly found in human plasma, revealed no interaction with naked and PVA-coated NLCs. These promising results allow considering further in vivo studies for efficient delivery of OXC.