The application of sunscreen is well known as an ultraviolet radiation (UVR) protective strategy, and modern sunscreens containing nanoparticles of titanium dioxide (TiO2) or zinc oxide (ZnO) offer consumers highly efficacious and aesthetically-pleasing options. Concern about the long-term safety of nanoparticles in sunscreens, however, has been voiced within some community sectors. In this study, immune-competent hairless mice received weekly topical applications of commercially-available sunscreens that contained nanoparticles of ZnO, a combination of TiO2 nanoparticles and organic UVR filters, only organic UVR filters, or no sunscreen at all, and were subsequently exposed to UVR. After 36 weeks, no statistically significant adverse biological outcomes were identified in mice receiving applications of the sunscreens containing ZnO or TiO2 nanoparticles. In contrast, mice receiving no applications of sunscreen followed by UVR exposure developed statistically significant incidences of histologically-diagnosed malignant and non-malignant skin neoplasms. Whilst the application of the sunscreen containing only organic filters was protective against UVR-induced skin neoplasms, substantial gene disregulation was noted in mice treated with the organic sunscreen, but not the ZnO- or TiO2 nanoparticle-containing sunscreens. Exposure to UVR did not have a significant impact on tissue concentrations of Zn or Ti. We propose that when considered alongside previous studies of shorter duration, the presence of metal oxide nanoparticles in sunscreens is no reason to avoid their use.