In order to find more excellent structural materials resistant to radiation damage, high-entropy alloys (HEAs) have been developed due to their characteristics of limited point defect diffusion such as lattice distortion and slow diffusion. Specially, refractory high-entropy alloys (RHEAs) that can adapt to a high-temperature environment are badly needed. In this study, TiZrHfNbMo0.1 RHEAs are selected for irradiation and nanoindentation experiments. We combined the mechanistic model for the depth-dependent hardness of ion-irradiated metals and the introduction of the scale factor f to modify the irradiation-hardening model in order to better describe the nanoindentation indentation process in the irradiated layer. Finally, it can be found that, with the increase in irradiation dose, a more serious lattice distortion caused by a higher defect density limits the expansion of the plastic zone.