To enhance the resistance of Saccharomyces boulardii (S.boulardii) to the environment, its microcapsule was prepared by compound wall materials. Based on the application of modified starches, β-cyclodextrin and gelatin as compound wall materials, the effect of the ratio of three blended wall materials was assayed on colony-forming units in S. boulardii microcapsules using the orthogonal experimental method. Then an optimization was performed concerning several spray drying processing parameters, such as compound wall material concentration, inlet temperature, air flow, and feeding speed via the single factor process and the orthogonal test. Further, corresponding morphology and tolerance to artificial digestive juice were observed. The results showed that the optimal ratio of modified starches, β-cyclodextrin and gelatin was 6∶3∶5 with the 10% concentration of S. boulardii. The optimal spray drying processing parameters were as follows: the compound wall material concentration of 16%, inlet temperature of 80℃, air flow of 550L/h, and feeding speed of 15mL/min. Besides, the leading influence factor on the production of S. boulardii microcapsules was inlet temperature, followed by compound wall material concentration and feeding speed, and finally air flow. Under those conditions, S. boulardii microcapsules were spherical without holes and cracks on the surface, and with an average size of 138.65μm. Moreover, S. boulardii microcapsules were also found to be good tolerance to artificial digestive juice, as well as slow-release in simulated gastrointestinal conditions. Collectively, the present study lays a foundation for the commercial production of S. boulardii microcapsules.