Spherical crystallization of water-insoluble drugs was investigated based on thermal-induced liquid-liquid phase separation (TILLPS) without the use of organic solvent. The phase diagram of the drug in water was constructed first, consisting of solid-liquid and liquid-liquid equilibrium regions. Within the liquid-liquid phase region, droplets of the solute-rich phase were formed and dispersed under appropriate agitation in the solvent-rich phase. After being stabilized by a surfactant, the solute-rich droplets can be converted to monodisperse spherical particles by performing quench cooling crystallization where the drug is crystallized within the confinement of the droplets. Furthermore, the influences of the oil droplets on the size of the resulting crystals were investigated, demonstrating that a decrease of the oil droplet size, controlled by agitation speed, would result in the decline of the product size. L-Menthol and ibuprofen products with a spherical shape and a yield of more than 95% were prepared successfully using the above method, revealing the application prospect of TILLPS in the drug spherical crystallization and it gives important guidance for the preparation of spherical particles of water-insoluble drugs.