Thermo-mechanical process of nickel-based oxide dispersion strengthened (ODS) superalloys is critical to produce desired components. In this study, an efficient method of consolidating powder is introduced to optimize the preparation process, microstructure and properties of nickel-based ODS superalloys. The influences of consolidation temperature, strain rate and ball milling time on the hardness of nickel-based superalloys were studied. The relationship among process, microstructure and hardness was established, the nanoparticles strengthening and grain boundary strengthening in nickel-based ODS superalloys were discussed. The results indicate that long ball milling time, moderately low consolidation temperature and high strain rates are beneficial to improving properties of nickel-based superalloys. Moreover, dispersion strengthening of nanoparticles and grain boundary strengthening play important roles in enhancing nickel-based ODS superalloys.