Nimesulide is a non-steroidal anti-inflammatory drug that acts through selective inhibition of COX-2 enzyme. Poor bioavailability of this drug may leads to local toxicity at the site of aggregation and hinders reaching desired therapeutic effects. This study aimed at formulating and optimizing topically applied lotions of nimesulide using an experimental design approach, namely response surface methodology. The formulated lotions were evaluated for pH, viscosity, spreadability, homogeneity and in vitro permeation studies through rabbit skin using Franz diffusion cells. Data were fitted to linear, quadratic and cubic models and best fit model was selected to investigate the influence of permeation enhancers, namely propylene glycol and polyethylene glycol on percutaneous absorption of nimesulide from lotion formulations. The best fit quadratic model explained that the enhancer combination at equal levels significantly increased the flux and permeability coefficient. The model was validated by comparing the permeation profile of optimized formulations’ predicted and experimental response values, thus, endorsing the prognostic ability of response surface methodology