The microstructural evolution of postirradiation annealing (PIA) and reirradiation in high‐dose proton‐irradiated Fe–Cu model alloys (Cu: 0.05 and 0.1 wt%) at high temperature (about ≈290 °C) is investigated using positron annihilation and nanoindentation. The positron results show that vacancy defects and Cu precipitates are produced in high‐dose proton‐irradiated Fe–Cu alloys. Under PIA at 500 °C, vacancy defects are recovered substantially, whereas Cu precipitates still remain in Fe–Cu alloys. After reirradiation, the S parameter in the damaged region evidently increases when compared with the postirradiation annealed samples. It is suggested that Cu precipitates remain in the postirradiation annealed samples that strongly affect the formation and growth of vacancy defects. More defects are produced in reirradiated samples, resulting in higher S parameters. The nanoindentation results show obvious hardening in the reirradiated samples. Both vacancy defects and Cu precipitates lead to the hardening of high‐dose proton‐irradiated Fe–Cu model alloys.