The damage behavior under low-energy and high-flux helium ions irradiation condition of the W28Ta28V28Zr8Sc8 high-entropy alloy, prepared by spark plasma sintering (SPS), is studied. The results show that the high-entropy alloy reveals better resistance to irradiation damage than pure W under the same He ions irradiation condition. Under different He ion energies, the He ions threshold energy when the serious “fuzz” structure appears in high-entropy alloy is much higher than that of pure W. With the same irradiation parameters, the “fuzz” layer thickness of high-entropy alloy is obviously smaller than that of pure W. After irradiation, the different phase regions of W28Ta28V28Zr8Sc8 high-entropy alloy show different surface morphology characteristics, which are related to the He ion irradiation behavior of the main elements constituting the phase region. An excellent irradiation damage resistant material could be achieved by designing the microstructure of the high entropy alloy.