Abstract The X‐ray activated persistent luminescence (PersL) observed in lanthanide‐doped nanoparticles has recently attracted widespread interest in both basic research and cutting‐edge applications. However, how to realize intense, rich, and color‐tunable PersL in nanoparticles has remained a challenge. Here a conceptual strategy is reported to enhance the X‐ray‐activated PersL of nanoparticles by minimizing the hydroxyl impurities inside the host lattice. This study shows that the anhydrides/acids treatment during synthetic procedures is able to reduce the hydroxyl impurities inside fluoride nanocrystal lattice markedly, and promote the formation of Frenkel defects by moving more F − ions from their lattice sites into interstitial sites under X‐ray irradiation. A mechanism is proposed to illustrate the enhancement of PersL in hydroxyl‐minimized nanoparticles. The radioluminescence is also enhanced, and the multimode luminescence in a single nanoparticle is further obtained by the core‐shell nanostructure design with temporally tunable multi‐colors output. These findings facilitate the development of small‐size X‐ray‐activated PersL nanomaterials and provide more opportunities for their frontier applications in optical storage, information identification, and flexible optical imaging.