Background: In present work Transdermal Nanoemulsion Gel of Dexibuprofen was optimized and developed by spontaneous emulsification using a probe sonicator (d-6mm, 20KHz). Pseudoternary phase research and Response surface methodology used to find best optimized formulation. Using Central composite design formulation batches were developed at three levels with two factors based on the appropriate oil concentrations and Smix (Surfactant: Co-Surfactant). The dependent variables average droplet size, entrapment efficiency, and percent drug release for each batch were examined. All batches exhibit globule size less than 200nm and followed Zero order drug release and as n>0.89, NonFickian (Super case II transport). Since samples obtained from different regions have almost identical refractive indices, the Nanoemulsion may be referred to as isotropic