Clofazimine displays high intersubject variability in absorption after oral administration because of its extremely low water solubility and high lipophilicity. The present investigation was aimed to prepare self micro emulsifying drug delivery system (SMEDDS) of clofazimine for improving its dissolution properties by using design of experiment (DoE) approach. Various lipid, surfactant, and co-surfactants were screened based on their ability to solubilize clofazimine and their ability to make a clear transparent microemulsion upon dilution with water. Based on these tests, Capmul MCM, Tween-20, and Labrasol were selected as lipid, surfactant, and co-surfactant respectively. The design batches were prepared according to simplex lattice design and the optimized batch was selected by using the desirability function of design expert software. Contour plots and response surface plots were generated to understand the effect changed in formulation composition on critical product parameters (globule size and cumulative percentage drug release in 30 min). All the prepared batches released more than 85% drug in less than 60 min in 1.2 pH HCl and 6.8 Phosphate buffer. The validity of the model was proved by observed close agreement between the experimentally obtained values for optimized batch and predicted values given by the polynomial equation. The present investigation successfully demonstrated the effectiveness of the simplex lattice design and desirability function for optimizing the SMEDDS formulation and its ability to explain the effects of formulation variables on critical product attributes.