In this paper, uniform hollow mesoporous GdF3 micro/ nanospheres were successfully prepared by a facile two-step synthesis route without using any surfactant, catalyst, and further calcination process. The precursor Gd(OH)CO3 spheres are prepared by a coprecipitation process. After that, uniform and size-tunable GdF3 hollow spheres were easily coprecipitated with NaBF4 at the sacrifice of the precursor with low temperature and short reaction time. X-ray diffraction, scanning electron microscopy, transmission electron microscopy, high-resolution TEM, N2 adsorption/desorption, and upconversion (UC) photoluminescence spectra were used to characterize the as-obtained products. It is found that the initial pH value and NaBF4/Gd3+ molar ratios play important roles in the structures, sizes, and phases of the hollow products. The growth mechanism of the hollow spheres has been systematically investigated based on the Kirkendall effect. Under 980 nm IR laser excitation, UC luminescence of the as-prepared Yb3+/Er3+-codoped GdF3 hollow spheres can be changed by a simple adjustment of the concentration of the Yb3+ ion. Enhanced red emission is obtained by introducing Li+ ions in GdF3:Yb3+/Er3+. Furthermore, a doxorubicin release experiment and a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide cytotoxicity assay reveal that the product has potential application in drug delivery and targeted cancer therapy.