This paper presents an experimental investigation of irradiation-induced evolutions in three different oxide dispersion strengthening (ODS) alloys. High-dose, dual beam Ni–He ion irradiations are carried out up to 700 °C. The significant dose-dependent changes in the ODS particle size and number density are documented and interpreted in terms of specific point defect transport mechanisms, from small angle neutron scattering, TEM, and pulsed low-energy positron system measurements combined. The corresponding micro-mechanical changes in the alloys are evaluated based on the indentation response, which is, in turn, interpreted in terms of related, sub-grain plasticity mechanisms. The room temperature tests (without dwell time) reveal that the microscale work-hardening rate increases with decreasing the particle number density and pronounced strain localization effect. The elevated temperature tests (up to 600 °C, with dwell time) show that the indentation creep compliance is mostly temperature-independent after irradiation up to 25 dpa at Tirr = 500 °C and markedly temperature-dependent, after irradiation beyond 40 dpa at Tirr = 600 °C. This effect is ascribed to particular creep mechanisms associated with indent-induced plasticity, i.e., high stress and high dislocation density conditions.