The oral administration of memantine as an anti-Alzheimer disease (AD) is associated with many side effects. In this study, new nonionic microemulsion containing memantine to target the brain via transdermal administration was evaluated compared to oral solution. The microemulsions were tested for physical characteristics such as rheological behaviour, droplet size and drug loading. In addition, the skin permeability was evaluated in vitro using Franz diffusion cells. Moreover, LC-MSMS was used to measure the plasma level and drug concentration in the brain after transdermal administration compared to oral administration. The loaded memantine microemulsion showed Newtonian viscosity and droplet size below 100 nm. Besides, a flux value as high as 0.6819 ±0.04873 mg/cm2h using ME2 (microemulsion) could be achieved. Furthermore, the estimated bioavailability was as follows 81.14% for transdermal administration. Moreover, the oral showed faster absorption than transdermal absorption. Also, transdermal showed a higher plasma concentration (Cmax 318.028 ng/h). And it had a higher mean residence time (11.345 h) and had the most constant level in plasma and brain. Transdermal had a longer half-life (15.62 h) than oral. The difference in brain level was found to be significant between oral solution and transdermal ME2. The loaded MEs are stable colloidal drug delivery systems that are potential carriers for transdermal administration to control the plasma level and reduce the side effects associated with oral administration. Based on these findings, it is reasonable to suggest that memantine-loaded microemulsion could be a promising approach for Alzheimer's disease as a transdermal drug delivery system.