The aim of this research was to study the potential of proniosomal gel for transdermal delivery. Donepezil HCl loaded proniosomal gels were prepared by the coacervation phase separation method using different nonionic surfactants (spans and tweens). The prepared Donepezil HCl proniosomal gels were evaluated for various parameters such as particle size (PS), drug entrapment efficiency percentage (EE %), and in vitro drug release. Donepezil HCl loaded proniosomal gel was prepared successfully by coacervation phase separation method. The prepared proniosomal gel exhibited desired entrapment efficiency and Particle size. It was found that B2 which chosen as a best formula according to entrapment efficiency, Particle size, and in vitro release study. It was found that B2 which contains high concentration of span 60 is the most appropriate surfactant for the preparation of proniosomes. In vitro release studies proved that the prepared proniosomal gel contains Donepezil HCl considered to be a successful topical transdermal drug delivery system and provide a sustained release of encapsulated drug. Furthermore, there was no significant change in EE % and PS of Donepezil HCl proniosomal gel after storage for 6 months.