A family of monodisperse YF3, YF3:Ce3+ and YF3:Ce3+/Ln3+ (Ln=Tb, Eu) mesocrystals with a morphology of a hollow spindle can be synthesized by a solvothermal process using yttrium nitrate and NH4F as precursors. The effects of reaction time, fluorine source, solvents, and reaction temperature on the synthesis of these mesocrystals have been studied in detail. The results demonstrate that the formation of a hollow spindle-like YF3 can be ascribed to a nonclassical crystallization process by means of a particle-based reaction route in ethanol. It has been shown that the fluorine sources selected have a remarkable effect on the morphologies and crystalline phases of the final products. Moreover, the luminescent properties of Ln3+-doped and Ce3+/Ln3+-co-doped spindle-like YF3 mesocrystals were also investigated. It turns out that Ce3+ is an efficient sensitizer for Ln3+ in the spindle-like YF3 mesocrystals. Remarkable fluorescence enhancement was observed in Ce3+/Ln3+-co-doped YF3 mesocrystals. The mechanism of the energy transfer and electronic transition between Ce3+ and Ln3+ in the host material of YF3 mesocrystals was also explored. The cytotoxicity study revealed that these YF3-based nanocrystals are biocompatible for applications, such as cellular imaging.