A facile biomolecule-assisted hydrothermal route followed by calcination has been employed for the preparation of monoclinic yttrium oxysulfate hollow spheres doped with other rare-earth ions (Yb³⁺ and Eu³⁺ or Er³⁺). The formation of hollow spheres may involve Ostwald ripening. The resulting hybrid materials were used for upconversion applications. The host crystal structure allows the easy co-doping of two different rare-earth metal ions without significantly changing the host lattice. The luminescent properties were affected by the ratio and concentration of dopant rare-earth metal ions due to energy transfer and the symmetry of the crystal field. The type of luminescent center and the crystallinity of samples were also shown to have a significant influence on the optical properties of the as-prepared products.