Vertical stirred mills (VSM) are widely used for powder processing in many situations like mechanical alloying preparation and raw material crushing and shaping. Many structural and operational parameters like stirrer helix angle and rotating speed have great significance on VSM performance, especially in a large industry-scale situation. Therefore, it becomes essential to investigate these parameters systematically to obtain high energy efficiency and good product quality. In this work, the discrete element method (DEM) was used to examine the effects of stirrer helix angle (α), stirrer diameter (d), and rotating speed (n) on the grinding performance in an industrial VSM, and then the response surface method (RSM) was employed for multi-objective optimization in the VSM. It is found that a media vortex phenomenon may happen near the stirring shaft. The media collisions are significantly influenced byα,d, andn. Through multi-objective optimization design (MOD), the power consumption (P) of the stirrer reduced by 8.09%. The media collision energy (E) increased by 9.53%. The energy conversion rate (R) rises by 20.70%. The collision intensity and frequency are both improved. This optimization method can help determine good operating parameters based on certain structures.