Highly luminescent, biocompatible, and water-dispersible monodispersed NaYF 4 :Ho,Yb,Li (YHYL) upconversion nanoparticles (NPs) entrapped into mesoporous silica (YHYL@m-SiO 2 ) have been prepared. The surface area of YHYL@ m-SiO 2 NPs is found to be 128 m 2 /g with pore sizes of 3−4 nm. To illustrate the use of these YHYL@m-SiO 2 NPs as drug (DOX) carriers, an in-depth analysis is conducted. In order to use these nanoparticles for targeted cancer therapy, folic acid (FA) is also chemically conjugated to them. The affinity of YHYL@m-SiO 2 -NH 2 -FA-DOX NPs with folate receptors (FRs) are proved by in vitro studies. To demonstrate the potential utility of DOX-loaded and folic acid−conjugated nanoparticles (YHYL@ m-SiO 2 -NH 2 -FA-DOX NPs) in targeted radionuclide therapy, these NPs are radiolabeled with 177 Lu, a β − -emitting radionuclide [T 1/2 = 6.65 d, E β (max) = 497 keV, E γ = 113 keV (6.4%), 208 keV (11%)] extensively used for targeted radionuclide therapy. It is experimentally established that the adsorption of 177 Lu on YHYL@m-SiO 2 -NH 2 -FA-DOX NPs follows a combination of Langmuir and Freundlich isotherm models and pseudo-second-order kinetics. Cell toxicity and apoptotic cell death studies are conducted for [ 177 Lu]Lu-YHYL@m-SiO 2 -NH 2 -FA-DOX NPs in the MCF-7 cell line, which demonstrated the therapeutic potential of the radiolabeled and drug-loaded formulation in an in vitro model.