The objectives of present study were to understand the effect of formulation variables of self-nanoemulsifying drug delivery system (SNEDDS) of rosuvastatin (RSV). Box-Behnken design in conjunction with desirability function was used to evaluate the main effect, interaction effect and quadratic effect of independent formulation variables that included amounts of Acconon 200 E6, Cremophor RH40, and Lipoxol 300. For a better understanding of the selected variables for the optimal performance of RSV SNEDDS, the models were presented as three-dimensional response surface graphs. A fresh batch of optimized formulations and were prepared with optimized levels of the independent variables to yield dependent variables (Y1-Y6) values that were remarkably close to the predicted values. Drug excipient compatibility studies using the Fourier transform infrared spectroscopy, differential scanning calorimeter and x-ray diffraction indicated the absence of any incompatibility between RSV and selected excipients. The transmission electron microscopy of selected optimized SNEDDS of RSV showed the spherical shape of globules with no signs of coalescence and precipitation of RSV. The study demonstrates the use of Box-Behnken design for the preparation of RSV SNEDDS. The desirable goals can be obtained by systematic formulation approach in minimum possible time.