Phosphogypsum (PG) is an industrial solid waste produced in the wet process of phosphoric acid, which piles up in large quantities and pollutes the environment. However, anhydrous phosphogypsum (APG) obtained by PG after ball milling and calcination can be used as filler for polymer materials after hydrophobic modification on the surface, to improve the comprehensive mechanical properties of the materials by toughening and strengthening the materials, and it is an effective way for the resource utilization of PG. In this study, taking APG as the main raw material and the activation index as the response value, the process conditions of hydrophobic modification of APG were optimized by single factor test and the response surface methodology. The results show that the mathematical model established by the response surface has a high fitting degree. NaOH concentration, KH570 dosage and reaction time have significant effects on the activation index, and the dosage of KH570 is the main factor affecting the modification. The optimal hydrophobic modification conditions of APG are as follows: NaOH concentration is 2.6 mol/L, KH570 dosage is 3.10 g, and the reaction time is 149 min. Under the optimal conditions, the activation index and contact angle of the modified APG are 0.968 9 and 84.51°, respectively.