The solubility of zaltoprofen in binary {2-methoxyethanol (ME) + ethyl acetate (EAC)/ethanol (ET), 2-ethoxyethanol (EE) + ethyl acetate (EAC)} from 278.15 to 323.15 K and 1,4-dioxane (Diox) + ethyl acetate (EAC)/ethanol (ET) from 288.15 to 323.15 K was determined using the dynamic method under 0.1 MPa. The Hansen solubility parameter provided a reasonable explanation for the dissolution behavior of zaltoprofen. Three new crystal forms appeared during the dissolution process. Then, the Jouyban-Acree model, the Jouyban-Acree-van't Hoff model, the Jouyban-Acree-Apelblat model, the Sun model, and the Ma model closely correlated with the measured solubility data. As a result, the Ma model and the Sun model provided better fitting. The basic data could provide support for industrial design and purification optimization process of zaltoprofen.