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Abstract The physicochemical nature of sesamol (logP 1.29; solubility 38.8 mg/mL) substantially enhances its tissue distribution, minimizing its brain delivery. Sesamol-loaded solid lipid nanoparticles (S-SLNs) with an average particle size of 122 nm and an entrapment efficiency of 75.9 ± 2.91% were developed. Biochemical and behavioral paradigms clearly established the superiority of orally administered S-SLNs. The same was confirmed evidently by scintigraphic images of rabbits administered radiolabeled SLNs and confocal microscopy of brain sections of rats administered similarly prepared SLNs with a fluorescent marker. This study indicates the special importance of using phosphatidylcholine (as co-surfactant) in the preparation of SLNs for improving memory deficits. The aim of the present work was to develop sesamol as a therapeutic agent for central nervous system derangements. [ABSTRACT FROM AUTHOR]