<p>High-entropy alloys (HEAs) exhibit the excellent elevated-temperature performance and irradiation resistance due to the important core effect of serious lattice distortion for impeding dislocation motion, as candidate materials for nuclear applications. Despite the growth of the nuclear power sector, the effects of high-temperature and high-dose irradiation-induced voids on the mechanical properties of HEA in higher power nuclear reactors remain insufficiently researched, hindering its industrial application. In this study, we establish a consistent parameterization crystal plastic constitutive model for the hardening and creep behaviors of HEA, incorporating the spatial distribution of void size and shape effects, in contrast to traditional creep models that rely on temperature-related fitting parameters of the phenomenological power law equation. The model matches well with experimental data at different temperatures and irradiation doses, demonstrating its robustness. The effects of irradiation dose, temperature, and degree of lattice distortion on irradiation hardening and creep behavior of void-containing HEA are investigated. The results indicate that HEA with high lattice distortion exhibits better creep resistance under higher stress loads. The yield stress of irradiated HEA increases with increasing irradiation dose and temperature. The creep resistance increases with increasing irradiation dose and decreases with increasing irradiation temperature. The increase in irradiation dose causes a specific morphological transformation from spherical to cubic voids. The modeling and results could provide an effective theoretical way for tuning the yield strength and alloy design in advanced HEAs to meet irradiation properties.</p>