In order to optimize the separation performance of the screw press and enable its water removal rate and production to meet the production requirements, the influencing rule of the interactive effect of multi-factor parameters on its separation performance was studied by numerical simulation and experimental means. The internal flow field of the screw press was simulated by Fluent software. The rotation speed of the screw axis, back pressure of the slag outlet, and initial water content were taken as influencing factors, and the water removal rate and production were taken as objective functions. The Box–Behnken method was used to analyze the influencing rules of the interactive factors on the water removal rate and production. The results show that the significant factors affecting the water removal rate of the screw press are in the following order: initial water content > back pressure > rotation speed. The significant factors affecting screw press production are in the following order: rotation speed > back pressure > initial water content. The optimal combination of process parameters for the screw press is an initial water content of 55%, a screw axis rotation speed of 30 r/min, and a 5 kPa back pressure at the slag outlet. The water removal rate of 48.9% and production of 234.2 kg/d were obtained.