Blue-emitting Ag(+)-, Cu(2+)-, and Mg(2+)-doped ZnSe nanoparticles (NPs) were successfully synthesized at 80 °C by the precipitation method by using mercaptopropionic acid (MPA) as a stabilizer. UV–visible and photoluminescence (PL) studies were applied to investigate their physicochemical properties. Their structural properties were confirmed by X-ray diffraction (XRD), Fourier transform infrared (FT-IR) and transmission electron microscopy (TEM). The size of the ZnSe: X-capped MPA showed a strong relationship with dopant metals. The diameters of the Mg-doped ZnSe and the Cu-doped ZnSe were 22–24 nm, while the Ag-doped ZnSe was halved, at about 13 nm. The photoluminescence was within a wavelength range of 400–550 nm. In addition, the PL intensities, as well as the photoluminescence quantum yields, were in the order of the decreasing ionic radii of the dopant metals (ZnSe:Ag < ZnSe:Mg < ZnSe:Cu). Furthermore, through the interaction with lysine, the PL intensity of the ZnSe:X was changed. Interestingly, the capacity of the ZnSe:Mg for lysine was significantly higher than that of other dopant metals. Moreover, the toxicity of the ZnSe:Mg was relatively insignificant toward the hMSCs (about 80% cell viability at 320 ppm), compared to the transition-metal dopant. Therefore, the ZnSe:Mg material could have great potential for bioapplications.