Multifunctional fillers are greatly required for dental resin composites (DRCs). In this work, a spray dryer with a three-fluid nozzle was applied for the first time to construct high-performance complex nanoparticle clusters (CNCs) consisting of different functional nanofillers for dental restoration. The application of a three-fluid nozzle can effectively avoid the aggregation of different nanoparticles with opposite zeta potentials before the spray drying process in order to construct regularly shaped CNCs. For a SiO₂–ZrO₂ binary system, the SiO₂–ZrO₂ CNCs constructed using a three-fluid nozzle maintained their excellent mechanical properties ((133.3 ± 4.7) MPa, (8.8 ± 0.5) GPa, (371.1 ± 13.3) MPa, and (64.5 ± 0.7) HV for flexural strength, flexural modulus, compressive strength, and hardness of DRCs, respectively), despite the introduction of ZrO₂ nanoparticles, whereas their counterparts constructed using a two-fluid nozzle showed significantly decreased mechanical properties. Furthermore, heat treatment of the SiO₂–ZrO₂ CNCs significantly improved the mechanical properties and radiopacity of the DRCs. The DRCs containing over 10% mass fraction ZrO₂ nanoparticles can meet the requirement for radiopaque fillers. More importantly, this method can be expanded to ternary or quaternary systems. DRCs filled with SiO₂–ZrO₂–ZnO CNCs with a ratio of 56:10:4 displayed high antibacterial activity (antibacterial ratio > 99%) in addition to excellent mechanical properties and radiopacity. Thus, the three-fluid nozzle spray drying technique holds great potential for the efficient construction of multifunctional cluster fillers for DRCs.