The development of xenon plasma focused ion-beam (Xe⁺ PFIB) milling technique enables site-specific sample preparation with milling rates several times larger than the conventional gallium focused ion-beam (Ga⁺ FIB) technique. As such, the effect of higher beam currents and the heavier ions utilized in the Xe⁺ PFIB system is of particular importance when investigating material properties. To investigate potential artifacts resulting from these new parameters, a comparative study is performed on transmission electron microscopy (TEM) samples prepared via Xe⁺ PFIB and Ga⁺ FIB systems. Utilizing samples prepared with each system, the mechanical properties of CrMnFeCoNi high-entropy alloy (HEA) samples are evaluated with in situ tensile straining TEM studies. The results show that HEA samples prepared by Xe⁺ PFIB present better ductility but lower strength than those prepared by Ga⁺ FIB. This is due to the small ion-irradiated volumes and the insignificant alloying effect brought by Xe irradiation. Overall, these results demonstrate that Xe⁺ PFIB systems allow for a more efficient material removal rate while imparting less damage to HEAs than conventional Ga⁺ FIB systems.