The development of upconversion luminescence that allows for multimodal imaging in terms of resolution and penetration depth using a single system is attracting increasing interest for use in clinical molecular imaging and diagnostics. In this study, a simple method for inducing high-intensity upconversion luminescence by doping Li+ ions in a core-shell-structured NaLuF4:Yb,Tm system was developed. The synergistic effects of Li+ doping and the shell layer enhanced the luminescence intensity by approximately 210 times. In vitro and in vivo experiments showed that the high-intensity luminescence of nanoparticles exhibited a depth penetration ability for biological tissue. Owing to the heavy atom effect of the Lu3+ ions, the nanoparticles, which had a size of 23 nm, showed good CT imaging performance when compared with a clinical contrast agent, in addition to allowing for deep tissue imaging. The excellent optical and CT imaging properties of the Li+-doped high-luminescence core-shell upconversion nanoparticles suggest that they are highly suited for use in both deep tissue fluorescence imaging and CT imaging for multimodal diagnosis.