Increasing the interface density in nuclear-material systems has been proposed to be a promising strategy for annihilating defects introduced by ion irradiation. The role of interface characteristics between the WTaTiVCr refractory high entropy alloy (RHEA) and metal tungsten (W) on the irradiation resistance is rather unclear because of the distinct defect energy that exists in these two kinds of materials. Here, the nano-crystalline and amorphous mixed structures were obtained in WTaTiVCr/W multilayers to investigate the irradiation tolerance and mechanical properties. After being exposed to a 60 keV helium (He) ion irradiation platform at a fluence of 1 × 1017 cm−2, the grain sizes in irradiated multilayers were slightly decreased from 12.4 nm to 7.2 nm with increasing individual thickness, which was explained from the perspective of He+ energy deposition. The dependence of bubble growth in multilayers on the individual thickness was disclosed based on the analysis of bubble size and its pressure in the RHEA and W layers. The phase structures and element distributions in WTaTiVCr/W multilayers were also revealed by the defect formation and crystallization. Also, a maximum irradiation hardening of 1.91 GPa in the RHEA(10)/W(7) multilayer was disclosed, and the irradiation hardening in the multilayers exhibited a decreasing trend with increasing monolayer thickness, and the corresponding mechanisms about the hardening behaviors in these multilayers were also discussed based on the interface density and irradiation-induced defects.