An ionic liquid (IL) (1-butyl-3-methylimidazolium tetrafluoroborate)-based route was introduced into the synthesis of novel spherical NaYF4 nanoclusters with the assistance of a microwave-accelerated reaction system. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution TEM (HRTEM), selected area electron diffraction (SAED), energy-dispersive X-ray spectroscopy (EDS) and upconversion (UC) luminescence spectroscopy were used to characterize the obtained products. Interestingly, these spherical NaYF4 nanoclusters with diameters ranging from 200 to 430 nm are formed by the self-assembly of small nanoparticles. The diameters of the nanoclusters could be easily tuned just by changing the amounts of the precursors. By conducting the control experiments with different ILs or precursors, it is proven that the ILs have played key roles, such as the solvents for the reaction, the absorbents of microwave irradiation, and the major fluorine sources for the formation of the NaYF4 nanocrystals. The UC luminescence properties of the Ln(3+) codoped NaYF4 were measured, and the results indicate that the nanoclusters obtained in Bmim BF4 exhibit excellent UC properties. Since this IL-based and microwave-accelerated procedure is efficient and environmentally benign, we believe that this method may have some potential applications in the synthesis of other nanomaterials.