The aim of this study is to investigate the impact of various mixtures of crosslinked polystyrene (CPS) and yttrium-stabilized zirconia (YSZ) beads (CPS:YSZ=0:1–1:0 v:v) on the breakage kinetics and energy consumption during the wet stirred media milling (WSMM) of fenofibrate (FNB, BCS II drug). Twenty WSMM experiments were conducted with various mixtures at different stirrer speeds (3000, 4000 rpm) and bead loadings (0.35, 0.50) with a suspension of 10% FNB, 7.5% HPC-L, 0.05% SDS. Laser diffraction, viscometry, XRPD, and PLM imaging were used for characterization. A new modified microhydrodynamic model considering bead packing was used to interpret the roles of different beads. The results showed YSZ beads provided faster breakage, which was supported by the microhydrodynamic results. On the other hand, CPS beads required lower stirrer power. When both cycle time and specific energy consumption were considered for process optimality, YSZ–CPS bead mixtures performed better than YSZ or CPS alone and the optimal bead mixture was found to depend on the stirrer speed and the bead loading.