Lanthanide-doped fluoride nanoparticles (NPs) exhibit tunable X-ray excited afterglow (XEA), holding great promise for autofluorescence-free flexible X-ray imaging. However, materials with low atomic numbers, while sensitive to low-energy X-ray photons, suffer from weak X-ray absorption coefficients. This poses a significant challenge in achieving high-performance XEA with minimized radiation risk. In this study, we enhance the low-energy XEA of lanthanide activators by engineering the interfacial defect formation energy (Ef) in CaF2-based heterogeneous core/shell nanoarchitectures. Mechanistic investigations demonstrate that a large lattice misfit between the core and shell reduces the interfacial defect Ef, facilitating the formation of Frenkel defects and significantly increasing XEA intensity after low-energy X-ray irradiation. Specifically, the heterogeneous CaF2:Tb@CaLuF5 core/shell NPs, with a misfit of 3.382 %, exhibit approximately ∼ 8.9 times higher XEA intensity compared to the CaF2:Tb@CaF2 homogeneous core/shell NPs at 10 kV. Furthermore, integrating the CaF2:Tb@CaLuF5 NPs into a flexible scintillation screen enables XEA-based delayed imaging with high spatial resolution, up to approximately 14.2 lp mm−1, and an autofluorescence-free background. These findings advance the development of superior low-energy XEA materials and pave the way for autofluorescence-free three-dimensional X-ray imaging.