High-entropy alloys (HEAs), known for their unique compositional complexity and exceptional mechanical properties, have garnered significant interest for applications in extreme environments, such as energy, aerospace and nuclear industries. However, a significant challenge in deploying HEAs in the nuclear energy sector is the current lack of data on the irradiation performance of HEAs. Nuclear Science User Facilities (NSUF), established in 2007 as a United States Department of Energy’s Office of Nuclear Energy (DOE-NE) first and only user facilities, operates as a consortium of 21 institutions and 65 partner facilities across the United States. It provides resources for irradiation studies, post-irradiation examinations, high-performance computing, and more for accelerating research in nuclear energy. The cutting-edge capabilities include neutron and ion irradiation, novel destructive and non-destructive techniques for radiation damage characterization, such as advanced diffraction techniques (X-ray, electron, or neutron) coupled to extreme environments; in situ observation of microstructural evolution under irradiation; in situ irradiation to monitor corrosive attack in coolant environments; in situ irradiation and mechanical testing; and test methods for synergistic effects of superimposed extreme environments (temperature, irradiation, stress, corrosion) on materials behaviors. This abstract presents some results collected from several projects supported by the NSUF program. These studies aimed to investigate the core properties of the proposed high-entropy materials, including the high entropy effect, lattice distortion, and sluggish diffusion in relation to radiation resistance, compared to the reference materials and conventional materials currently used in nuclear reactors through consistent irradiation experiments. It will discuss ion-irradiation results of various HEAs, including single phase (face centered cubic (FCC), body centered cubic (BCC)), dual-phase (FCC+BCC), refractory, lightweight, oxide dispersion strengthening (ODS) HEAs, as well as high entropy ceramics. The materials were manufactured by arc melting, spark plasma sintering (SPS), and Directed Energy Deposition (DED). The effects of ion irradiation on microstructural evolution (e.g., dislocations, loops, and nanoclusters), phase stability, and deformation mechanisms were examined using advanced characterization techniques, including in situ Transmission Electron Microscopy (TEM), Energy Dispersive Spectroscopy (EDS), Atom Probe Tomography (APT), and nanoindentation. Results reveal that the distinct properties of high entropy materials, such as phase stability, fine grain structures, and tailored chemical compositions, play a critical role in mitigating radiation-induced defects. For example, dual-phase and ODS HEAs exhibit enhanced resistance to defect accumulation and void swelling, attributed to their microstructural heterogeneity and the presence of dispersed oxide particles. Lightweight HEAs demonstrated defect recombination mechanisms that reduce irradiation-induced damage. Furthermore, high-entropy ceramics showed superior resistance to amorphization and retained their mechanical integrity under extreme conditions. During cryogenic irradiations, single-phase FCC and BCC HEAs have been observed to accumulate surviving point defects at rates slower than their less compositionally complex counterparts. Moreover, studies on single-phase FCC HEAs and 316H stainless steel indicate that the radiation tolerance of HEAs is more pronounced at higher irradiation temperatures, highlighting in the potential of HEAs for use in advanced reactors operating at elevated temperatures. This comprehensive study highlights the potential of high-entropy materials as advanced structural materials for next-generation nuclear systems and provides valuable insights into the correlation between material design and irradiation resistance. This abstract also highlights the critical role of NSUF in advancing HEAs research for high-temperature and radiation-resistant applications.