Background: Alzheimer__ampersandsignrsquo;s disease is the main reason for dementia among the older section of the community. Administration of drugs through oral route to the patients suffering from neurological disorders is a serious challenge. Intranasal pharmacotherapeutics is an integral part of the modern drug delivery module used as an alternative way due to several therapeutic advantages. Objective: The objective of this current research was to develop intranasal mucoadhesive microspheres of anti-Alzheimer__ampersandsignrsquo;s drug donepezil HCl. Methodology: The formulations were prepared using gellan gum polymer in various drug: polymer ratios from 1:1 to 1:4 by emulsification cross-linking technique with an intention to enhance the onset of action, increase the drug bioavailability, and also to overcome the major obstacle blood-brain barrier. The prepared mucoadhesive microspheres were evaluated in terms of drug loading, entrapment efficiency, ex vivo drug permeation, histopathological characteristics, in vitro drug release, in vitro mucoadhesion, morphology, particle size, production yield, and swelling property. The prepared intranasal microspheres were characterized by differential scanning calorimetry, scanning electron microscopy, and X-ray diffraction study. Result: The fabricated intranasal microspheres had good spherical nature and excellent swelling property with entirely smooth surfaces. After reaching the nasal mucosa, the mucoadhesive microspheres formulations come in contact with the nasal fluid (containing cations), spontaneous viscous gelation (decreases the clearance rate) occurs in the nasal cavity, and the activity enhances several-folds by elevating the residence duration. Conclusion: This study opened new avenues for enhancing the pharmaceutical efficacy of donepezil HCl in Alzheimer__ampersandsignrsquo;s patient through intranasal route.