This study investigated the significance of process parameters in the rapid expansion of supercritical solution (RESS) for microparticle production of ipriflavone by using a two-level (2k) factorial design. Four process parameters, namely the extraction temperature (A), extraction pressure (B), pre-expansion temperature (C), and postexpansion temperature (D), of RESS were studied. The mean particle size data and results of analysis of variance revealed that the effect of C and the cross-interaction effect of AD and BD were significant in the process. The trends of these significant effects were evaluated through crystallization kinetics. After the RESS was performed, ipriflavone exhibited a considerably reduced mean size of 3 μm and a flake-like habit. In addition, differential scanning calorimetry and powder X-ray diffraction revealed that the crystal form of ipriflavone remained unchanged after RESS.