Radiation stability is often a key limiting factor in performance of fluorite-structured materials and determining their suitability for use in energy-related applications. In an effort to mitigate the effects of radiation, nanostructured materials are of interest as they incorporate high defect sink strengths [Rose et al., Nanostructured Materials (1995), Nita et al., Journal of Nuclear Materials (2004)]. Recently, it has been shown that the response of CeO2, ThO2, and UO3 to highly ionizing radiation is strongly dependent on the material’s redox response [Tracy et al., Nature Communications (2015)]. When exposed to swift heavy ions, cations in the material are subject to changes in valence which drives swelling and microstrain as irradiation-induced defects accumulate. In this work, we present new insights into how crystallite size affects irradiation-induced redox response and defect accumulation in fluorite-structured simple oxides. Using 946 MeV Au ions at the UNILAC accelerator of the GSI Helmholtz Center, we irradiated microcrystalline and nanocrystalline materials of different compositions containing cations known to reduce (CeO2), remain univalent (ThO2), and oxidize (UO2) under ionizing conditions. Irradiated samples were characterized by synchrotron X-ray diffraction/absorption, neutron total scattering with pair distribution function (PDF) analysis, transmission electron microscopy, and Raman spectroscopy. Each composition exhibits a distinct response between microcrystalline and nanocrystalline forms, such as magnitude of volumetric swelling and secondary phase formation, driven mainly by redox processes. PDF analysis reveals small peroxide-like defects in CeO2 and mono- and di-interstitial clusters in UO2. Our findings imply that nanocrystallinity has negative effects on a material’s response to highly ionizing radiation. These results shed more light onto the interplay of particle size and cation redox behavior and their effect on defect production in an important class of materials, an insight that is essential in developing advanced materials for energy-related applications.