Hollow La2O3:Ln (Ln = Yb/Er, Yb/Ho) microspheres with up-conversion (UC) luminescence properties were successfully synthesized via a facile sacrificial template method by employing carbon spheres as hard templates followed by a subsequent heating process. The structure, morphology, formation process, and fluorescent properties are well investigated by various techniques. The results indicate that the hollow La2O3:Ln microspheres can be well indexed to the hexagonal La2O3 phase. The hollow La2O3:Ln microspheres with uniform diameter of about 270 nm maintain the spherical morphology and good dispersion of the carbon spheres template. The shell of the hollow microspheres consists of numerous nanocrystals with the thickness of approximately 40 nm. Moreover, the possible formation mechanism of evolution from the carbon spheres to the amorphous precursor and to the final hollow La2O3:Ln microspheres has also been proposed. The Yb/Er and Yb/Ho codoped La2O3 hollow spheres exhibit bright up-conversion luminescence with different colors derived from different activators under the 980 nm NIR laser excitation. Furthermore, the doping concentration of the Yb3+ is optimized under fixed concentration of Er3+/Ho3+. This material may find potential applications in drug delivery, hydrogen and Li ion storage, and luminescent displays based on the uniform hollow structure, dimension, and UC luminescence properties.