A series of Co2+:ZnSe and Co2+:ZnSe/ZnSe nanocrystals emitting mid-infrared (mid-IR) fluorescence centered at around 3.4 and 4.7 μm were successfully synthesized via a simple hydrothermal method. The core/shell structure and post-heat treatment under reducing atmosphere were adopted to decrease the nanocrystal's surface quenching centers and defects and improve the mid-IR photoluminescence. By analysis of the X-ray diffraction, X-ray photoelectron spectroscopy, energy-dispersive X-ray spectroscopy, transmission electron microscopy (TEM), high-resolution TEM, Fourier transform IR, absorption, and mid-IR emission measurements of serial concentrations of Co2+-doped ZnSe nanocrystals, the crystal phase, grain size, core/shell structure, distribution of Co2+ ions, impurities on the surface, and mid-IR emission performance were investigated in detail. By use of optimum Co2+ concentration, core/shell structure construction, and proper post-heat treatment, the mid-IR emission intensities of nanocrystals were enhanced by an order of magnitude, and the nanocrystals showed excellent dispersibility. These high-quality optically active nanomaterials have potential uses in mid-IR devices such as composite fiber amplifiers and hot-pressed ceramic laser materials. © 2019 American Chemical Society.