The present study was designed with an aim to develop and optimize naproxen proniosomes (NAPRNs) using Box-Behnken Design (BBD). The formulation was optimized using three independent variables [maltodextrin (X), surfactant concentration (X) and drug concentration (X)] at three different levels (low, medium and high). The prepared fifteen formulations were evaluated for drug entrapment efficiency, vesicle size and transdermal flux to select the optimized naproxen niosomes (NAPRNopt). The developed NAPRNs formulations showed the nano-size vesicle (218-417 nm) and high encapsulation efficiency (60.48-92.48%) with high flux value (23.17-27.37 µg/cm/h). The formulation NAPRNopt has shown the vesicle size of 376.12 ± 4.12 nm with entrapment efficiency 86.43 ± 3.63% and transdermal flux of 27.56 ± 1.43 µg/cm/h. The SEM study revealed the formulation NAPRNopt showed irregular surface morphology of niosomes. The formulation NAPRNopt gel showed biphasic release behaviour as an initial fast release and later slower release with the Higuchi release mechanism. The anti-inflammatory study results showed a better effect than the standard NAP gel in the rat model.