This study investigates the effect of irradiation on the mechanical properties of a Ni-based superalloy, X-750. 40 MeV Ni + ions were used to irradiate the X-750 up to 1 dpa with and without 5000 appm helium pre-implantation at room temperature and 400°C. Nano-indentation hardness tests were carried out at room temperature in the depth range of 200 to 1400 nm before and after irradiation. Cross-sectional TEM observations were performed on the irradiated materials to correlate the mechanical results with the microstructural evolution. The results show that helium pre-implantation enhances the irradiation-induced hardening due to generating a high density of small cavities and promoting the formation of larger Frank loops. In addition, nano-scale mechanical tests reveal that changing the subsequent Ni ion irradiation temperature from room temperature to 400°C, leads to changing of the mechanical response from a softening behavior to an irradiation-induced hardening. The c¢ precipitates became disordered after irradiation at room temperature, whereas the c¢-phase remained ordered during irradiation at 400°C. The softening effect of the c¢ instability outweighed the hardening impact of irradiation-induced defects such as cavities and Frank loops, leading to a hardness reduction for the room-temperature-irradiated material. Three different obstacle-hardening models were employed to assess the individual impact of each type of defect on the material's overall strength enhancement. Furthermore, the superposition principle was used for each model to estimate the overall irradiation-induced strengthening, which is compared to the results from the nano-hardness measurements.