The inorganic filler is the main component of dental resin composite, which is very important for the properties of resin composite. In this paper, ZnO mesocrystals with porous and hierarchical structure were achieved by a thermal hydrolysis method using gum arabic as structure-directing agent. The thickness and diameter of the synthesized ZnO mesocrystals were about 1.2 μm and 1.0 μm. The amorphous silica in a thickness of 4~6 nm was uniformly coated on the surface of ZnO mesocrystals via the microfluidc process. ZnO mesocrystals were characterized by field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). The ZnO@SiO2 was firstly modified with 3-methacryloxypropyl trimethoxysilane (γ-MPS), and mixed with modified SiO2 nanoparticles as co-filler. Subsequently modified inorganic particles were added into Bis-GMA/TEGDMA to prepare dental composite resin by light-curing. The mechanical testing show that the mass fraction of ZnO@SiO2 (≤5%) could improve the mechanical properties of composite resin effectively. The silica matrix composite resin filled with 3% ZnO@SiO2 demonstrates the best mechanical properties, among which the flexural strength, flexural modulus and compression strength increase by 12.9%, 6.6% and 3.7%, respectively, in comparison with the composite using of only SiO2 filler. This optimal composite also exhibits superior antimicrobial activity, with antibacterial rate up to 98.7% to Streptococcus mutans. In addition, the composite resin with ZnO@SiO2 also has better wear resistance.