19F magnetic resonance imaging (MRI) probes that can detect biological phenomena such as cell dynamics, ion concentrations, and enzymatic activity have attracted significant attention. Although perfluorocarbon (PFC) encapsulated nanoparticles are of interest in molecular imaging owing to their high sensitivity, activatable PFC nanoparticles have not been developed. In this study, we showed for the first time that the paramagnetic relaxation enhancement (PRE) effect can efficiently decrease the 19F NMR/MRI signals of PFCs in silica nanoparticles. On the basis of the PRE effect, we developed a reduction‐responsive PFC‐encapsulated nanoparticle probe, FLAME‐SS‐Gd3+ (FSG). This is the first example of an activatable PFC‐encapsulated nanoparticle that can be used for in vivo imaging. Calculations revealed that the ratio of fluorine atoms to Gd3+ complexes per nanoparticle was more than approximately 5.0×102, resulting in the high signal augmentation.