Purpose: The aim of this study was to investigate the effect of various mass fractions of 10-methacry-loyloxydecyl dihydrogen phosphate (MDP)-conditioned or unconditioned zirconia nano- or micro-particles with different initiator systems on the mechanical properties of nanohybrid resin composites. Methods: Both light-cured (L) and dual-cured (D) resin composites were prepared. When the mass fraction of the nano- or micro-zirconia fillers reached 55 wt%, resin composites were equipped with dual-cured initiator systems. We measured the three-point bending-strength, elastic modulus, Weibull modulus and translucency parameter of the nanohybrid resin composites containing various mass fractions of MDP-conditioned or unconditioned zirconia nano- or micro-particles (0%, 5 wt%, 10 wt%, 20 wt%, 30 wt% and 55 wt%). A Cell Counting Kit (CCK)-8 was used to test the cell cytotoxicity of the experimental resin composites. The zirconia nano- or micro-particles with MDP-conditioning or not were characterized by transmission electron microscopy (TEM), Fourier infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). Results: Resin composites containing 5– 20 wt% MDP-conditioned or unconditioned nano-zirconia fillers exhibited better three-point bending-strength than the control group without zirconia fillers. Nano- or micro-zirconia fillers decreased the translucence of the nanohybrid resin composites. According to the cytotoxicity classification, all of the nano- or micro-zirconia fillers containing experimental resin composites were considered to have no significant cell cytotoxicity. The FTIR spectra of the conditioned nano- or micro-fillers showed new absorption bands at 1719 cm^{− 1} and 1637 cm^{− 1}, indicating the successful combination of MDP and zirconia particles. The XPS analysis measured Zr–O–P peak area on MDP-conditioned nano- and micro-zirconia fillers at 39.91% and 34.89%, respectively. Conclusion: Nano-zirconia filler improved the mechanical properties of nanohybrid resin composites, but cannot be the main filler to replace silica filler. The experimental dual-cured composites can be resin cements with better opacity effects and a low viscosity.