In this study, the O/W emulsification processes with the natural surfactants that were extracted from Medicago sativa L. and Sapindus saponaria L. as emulsifiers were optimized using the central composite design-response surface methodology (CCD-RSM). Herein, independent parameters were the amounts of mixed emulsifiers, the mixing ratio of natural emulsifiers (soapberry saponin/alfalfa saponin), and the emulsification time, whereas the reaction parameters were the emulsion stability index (ESI), mean droplet size (MDS), and antioxidant activity (DPPH radical scanvenging activity). Through basic experiments, the ranges of operation variables for the amount of mixed emulsifiers, the mixing ratio of natural emulsifiers, and the emulsification time were 12~14 wt%, 30~70%, and 20~30 min, respectively. The optimum operation variables deduced from CCD-RSM for the amount of mixed emulsifiers, the mixing ratio of natural emulsifiers, and the emulsification time were 13.2 wt%, 44.2%, and 25.8 min, respectively. Under these optimal conditions, the expected values of the ESI, MDS, and antioxidant activity were 88.7%, 815.5 nm, and 38.7%, respectively. And, the measured values of the ESI, MDS, and antioxidant activity were 90.6%, 830.2 nm, and 39.6%, respectively, and the average experimental error for validating the accuracy was about 2.1%. Therefore, it was possible to design an optimization process for evaluating the O/W emulsion process using CCD-RSM.