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The oral administration of donepezil hydrochloride has low brain targeting efficiency especially due to the presence of the blood–brain barrier leading to poor quality of treatment. Hence, this study aimed to systematically design chitosan nanoparticles for direct nose-to-brain delivery of donepezil hydrochloride using the Quality by Design approach for better transport to the brain avoiding the blood–brain barrier. The optimized formulation showed 180.2 nm average particle size and 0.282 polydispersity index, + 16.6 mV zeta potential, more than 90% drug release, and more than 70% drug permeation in 24 h. The studies on in-vitro drug release and ex-vivo permeation showed a sustained release pattern fulfilling Korsemeyer Peppa's model. The confocal laser scanning micrographs showed the spherical nature of nanoparticles. The intranasal administration of donepezil hydrochloride nanoparticles in Wistar rats showed approximately 2.6 times more drug than donepezil hydrochloride solution given intranasally and approximately 10 times more drug than donepezil hydrochloride solution given orally in the brain respectively after 6 h. Further, confocal micrographs using Rhodamine B (fluorescent dye) loaded nanoparticles confirmed the localization of nanoparticles in the brain post-intranasal administration. The obtained results suggested that the chitosan nanoparticles are promising drug carriers for the nose-to-brain delivery of donepezil hydrochloride for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]