Water-soluble hexagonal NaScF4:Yb/Er nanocrystals have been directly synthesized via a facile one-step hydrothermal route. The as-prepared nanocrystals were monodisperse and could form stable colloidal solutions in polar solvents, such as water and ethanol. The novel NaScF4:Yb/Er nanocrystals exhibited intrinsic intense red upconversion emission, in contrast to other lanthanide-doped fluoride nanocrystals. Remarkably, the upconversion emission intensity was enhanced ∼6.8 times through the coating of an active-shell (containing Yb(3+)) surrounding the NaScF4:Yb/Er core nanocrystals, owing to surface passivation effect and efficient energy transfer from Yb(3+) ions in both the core and the shell to Er(3+) ions. These water-soluble hexagonal NaScF4:Yb/Er nanocrystals with intense red emission are ideal for a variety of in vitro and in vivo biological imaging applications.