The crystallization process of erythromycin ethylsuccinate in a tetrahydrofuranwater system was investigated. Results show that oiling out occurs under several conditions; hence, a phase diagram with a liquid-liquid equilibrium area was established experimentally. For improved understanding of oiling-out crystallization, a series of in-situ tools, including FBRM, ATR-FTIR, and PVM, were applied to monitor the oiling-out phenomenon and the subsequent nucleation of erythromycin ethylsuccinate. SEM images were employed to analyze the influence of oiling out on the properties of the final crystals. The nucleation mechanism of erythromycin ethylsuccinate differs significantly depending on the location of the line of operation.The combination of cooling method and anti-solvent crystallization can be achieved with fundamental data of the phase diagram to suppress the oiling out phenomenon and obtain crystal products with high quality. The ternary phase diagram is of great importance in the process design of anti-solvent crystallization for an oiling-out system.