The targeted irradiation of structures by X-rays has seen application in a variety of fields. Herein, the use of 5–10 nm LiF nanoparticles to locally enhance the degradation of an organic thin film, diindenoperylene, under hard X-ray irradiation, at relatively low ionizing radiation doses, is shown. X-ray reflectivity analysis indicated that the film thickness increased 12.04 Å in air and 11.34 Å in a helium atmosphere, under a radiation dose of ∼65 J/cm2 for 3 h illumination with a bi-layer structure that contained submonolayer coverage of thermally evaporated LiF. This was accompanied by significant modification of the surface topography for the organic film, which initially formed large flat islands. Accelerated aging experiments suggested that localized heating was not a major mechanism for the observed changes, suggesting a photochemical mechanism due to the formation of reactive species from LiF under irradiation. As LiF has a tendency to form active defects under radiation across the energy spectrum, this could could open a new direction to explore the efficacy of LiF or similar optically active materials that form electrically active defects under irradiation in various applications that could benefit from enhanced activity, such as radiography or targeted X-ray irradiation therapies.