The aim of this study was to design and optimize a nano-transfersomes of Diclofenac diethylamine (DDEA) and Curcumin (CRM). A 3(3) factorial design (Box-Behnken) was used to derive a polynomial equation (second order) to construct 2-D (contour) and 3-D (Response Surface) plots for prediction of responses. The ratio of lipid to surfactant (X1), weight of lipid to surfactant (X2) and sonication time (X3) (independent variables) and dependent variables [entrapment efficiency of DDEA (Y1), entrapment efficiency of CRM (Y2), effect on particle size (Y3), flux of DDEA (Y4), and flux of CRM (Y5)] were studied. The 2-D and 3-D plots were drawn and a statistical validity of the polynomials was established to find the compositions of optimized formulation. The design established the role of the derived polynomial equation, 2-D and 3-D plots in predicting the values of dependent variables for the preparation and optimization of nano-transfersomes for transdermal drug release.