Refractory high-entropy alloys (RHEAs) are candidate structural materials for nuclear applications due to their promising high-temperature mechanical performance and irradiation tolerance. However, most body-centered cubic (BCC) RHEAs form additional phases depending on their thermal history, with few studies assessing their effect on irradiation tolerance. This study characterizes the impact of phase transformations on the room-temperature irradiation tolerance of a nanocrystalline TiZrNbHfTa RHEA by assessing its microstructure and micromechanical properties before and after thermal treatments between 500 and 800 °C. The alloy demonstrates exceptional irradiation tolerance before and after 500 °C treatments for 1–100 h, which induce BCC to hexagonal close-packed (HCP) phase transformation, with excellent microstructural stability and minimal irradiation-induced hardening. Conversely, 800 °C treatment for 1 h forms two major BCC phases and a minor HCP phase, negatively impacting both pre- and post-irradiation mechanical performance and causing significant irradiation-induced hardening and embrittlement. Additionally, this research identifies a second HCP phase in the 500 °C, 100 h-treated condition, marking its first mention in the literature. This study emphasizes the importance of assessing temperature and phase formation effects on the irradiation tolerance of RHEAs for future nuclear reactors.