Recent technologies, such as nanotechnology, provide new opportunities for next generation scintillation devices and instruments. New nanophosphor-based materials seem to be promising for further improvements in optical diffusion studies. In medical imaging, detector technology has found widespread use, offering improved signal capabilities. However, in spite of many spectacular innovations and the significant research in chemical synthesis on the detective material, improvement in signal quality is still an issue requiring further progress. Here, a sophisticated analysis is shown within the framework of Mie scattering theory and Monte Carlo simulation which demonstrates the optimum structural and optical properties of nanophosphors that are significantly promising in manufacture for further signal modulation improvement. A variety of structural and optical properties were examined: (1) phosphors of grain size (1 to 1000 nm), (2) packing density (50% to 99%), (3) light wavelength (400 to 700 nm), and (4) refractive index of nanophosphor (real part: 1.4–2.0, imaginary part: ). Results showed that for a specific thickness of nanophosphor layer, the compromise between spatial resolution and sensitivity can be achieved by optimizing the structural () and optical properties of the nanophosphor (). Finally, high optical modulation was accomplished employing grains of high refractive index and size above 200 nm.