Nickel and Helium ion implantation-induced hardening and microstructural evolution of X750 in the heat-treated (HT) and solution annealed (SA) conditions were investigated using nano-indentation hardness testing and electron microscopy (scanning electron microscopy (SEM) and transmission electron microscopy (TEM)). Irradiation crystal damage up to ψ = 5 dpa was invoked with Ni+ implantation while He+ implantation up to CHe = 5000 appm was performed on samples the HT and SA conditions. The X750 alloy displayed generally increasing hardness with increasing Ni+ implantation damage but a perturbation in the trend occurred when ψ ≤ 0.5 dpa, and the hardness dropped by about 30% and 2% for the HT and the SA samples, respectively. TEM analysis indicated that this softening was associated with disordering and dissolution of the γ′ strengthening phase. The hardening behavior observed at higher implantation damage (ψ = 1 dpa) resulted in reformation of Al/Ti-rich regions within the microstructure phase. The hardness of the X750 increased continuously with increasing implanted He+ up to CHe = 1000 appm. This was associated with the formation of helium bubbles as observed by TEM. Slight drop in hardness in the HT condition at CHe = 5000 appm indicated that high levels of He+ implantation destabilize the γ′ precipitates as was confirmed with TEM observed disappearance of γ′ super-lattice reflections.