The nickel-based NiMo–Y2O3NP alloy has been identified as a potential structural material to be used for advanced reactors. In this study, the microstructural evolution behavior of oxide-dispersion-strengthened NiMo–Y2O3 alloys irradiated with He+ ions possessing different incident particle energies (0.5, 1.0, and 2.0 MeV) was investigated by transmission electron microscopy, simulation calculations, and nanoindentation tests. The experimental results showed that helium bubbles were generated in all three irradiated samples of the NiMo–Y2O3NP alloy, where more than half of the bubbles were smaller than 4 nm in diameter. As the energy of the incident He+ irradiating ion increased, the number density of helium bubbles decreased, but their average size increased within the tolerance of the error, inducing an increase in the volume fraction of helium bubbles in the damage peak region. This could be attributed to the decrease in helium concentration and increase in the ratio of vacancies to helium atoms (Vac./He) in helium bubbles in the damage peak region. In addition, the average nanohardness of the irradiated samples S1, S2, and S3 was higher than that of the unirradiated sample S0. In this study, we evaluated the effects of He+ irradiating ion energy on the evolution behavior of helium bubbles in the alloy, providing a reference for further research on the evolution behavior of helium-induced damage defects of structural materials.