Solution-mediated polymorphic transformation (SMPT) exists extensively in crystallization from solution in many polymorphic systems. To obtain the desired products, it is crucial to understand the mechanism of the SMPT process and then to develop a regulation strategy for it. However, the mechanism of SMPT of different polymorphs is still not well understood. In this work, the mechanism and control strategy of SMPT were studied in detail by using 5-nitrofurazone as a model compound. A series of SMPT experiments were carried out. Different 5-nitrofurazones form beta (different sizes or with different amounts of impurities/additive) can (1) transform to form alpha directly, or (2) transform to form gamma directly, or (3) initially transform to mixture of form alpha and form gamma and then finally transform to form gamma. Then, the mechanism of the SMPT process of 5-nitrofurazone was explored by using quantum chemical calculation, solubility determination, lattice energy calculation, single crystal indexing, and lattice matching calculation. Finally, the regulation strategy of the SMPT process of 5-nitrofurazone was proposed: form a can be obtained through decreasing size of form beta. Form gamma can be directly obtained through the addition of a certain amount of 5-nitrofurfural.