Imaging-guided photothermal therapy based on functional nanomaterials has recently received signifi cant attention and the selection of functional materials with optimal imaging and therapy effect is extremely important. In this work, NaDyF4-based nanoparticles with varying size are synthesized by doping with different amounts of lutetium ions. To obtain an optimized material, the influence factor of magnetic resonance, X-ray attenuation, and photothermal properties are discussed in detail. Then, NaDyF4:50%Lu@Prussian blue (PB) nanocomposite is selected as the optimal functional material for T-1- and T-2-weighted magnetic resonance imaging, X-ray computed tomography, and photothermal imaging-guided photothermal therapy of tumor on a small animal model, and the treatment is applied with good results. Studies also suggest that the NaDyF4:50%Lu@PB nanocomposites are biocompatibile. The selection of an optimal material from a multi-perspective study has provided an incentive for the development of an assortment of novel multifunctional materials for early cancer multifunctional diagnosis and imaging-guided photothermal therapy.