Bombardment of materials by high-energy particles (e.g., electrons, nuclei, X-and γ-ray photons) often leads to light emission, known generally as scintillation. Scintillation is ubiquitous and enjoys widespread applications in many areas such as medical imaging, X-ray non-destructive inspection, night vision, electron microscopy, and high-energy particle detectors. A large body of research focuses on finding new materials optimized for brighter, faster, and more controlled scintillation. Here, we develop a fundamentally different approach based on integrating nanophotonic structures into scintillators to enhance their emission. To start, we develop a unified and ab initio theory of nanophotonic scintillators that accounts for the key aspects of scintillation: the energy loss by high-energy particles, as well as the light emission by non-equilibrium electrons in arbitrary nanostructured optical systems. This theoretical framework allows us, for the first time, to experimentally demonstrate nearly an order-of-magnitude enhancement of scintillation, in both electron-induced, and X-ray-induced scintillation. Our theory also allows the discovery of structures that could eventually achieve several orders-of-magnitude scintillation enhancement. The framework and results shown here should enable the development of a new class of brighter, faster, and higher-resolution scintillators with tailored and optimized performances − with many potential applications where scintillators are used.