Objective To determine the optimized self micro-emulsifying drug delivery system (SMEDDS) formulation of probucol. Methods According to the indexes of mean particle size, zeta-potential, solubility of probucol in blank SMEDDS and the dissolution percentage in 5 minutes of the preparations, the optimized formulation was determined by the central composite design-response surface methodology. Results When the correspondent percentage of olive oil in oil phase (W/W) was 0.33, the percentage of oil phase in formulation (W/W) was 0.5, and the ratio of surfactant to co-surfactant (W/W) was 2.0, respectively. The mean particle size, zeta-potential, solubility of probucol and dissolution percentage in 5 minutes of micro-emulsion was 92.7 nm, -17.38 mV, 65.17 mg/mL and 63.46%, respectively. Conclusions The optimized formulation of the probucol SMEDDS was obtained quickly and conveniently by the central composite design-response surface methodology. The method had a reliable predictability.