Colloidal ZnS:Mn nanocrystals (NCs) were synthesized in water by capping the NC surface with conventional amino acids: L-cysteine (Cys) and L-serine (Ser) molecules, which have very similar structures but different terminal functional groups. The optical properties were investigated by using UV-Visible and photoluminescence (PL) spectroscopy. The PL spectra for both ZnS:Mn-Cys and ZnS:Mn-Ser NCs showed broad emission peaks at 590 nm. The measured average particle size from the high-resolution transmission electron microscopy (HR-TEM) images were 4.38 nm (ZnS:Mn-Cys) and 5.57 nm (ZnS:Mn-Ser), which were also supported by Debye-Scherrer calculations. In addition, the surface charge of the NCs in aqueous solutions were measured using zeta-particle size analyzer spectroscopy, which showed formation of negatively charged surface for the ZnS:Mn-Cys (-43.93 mV) and ZnS:Mn-Ser (-8.21 mV) NCs in water. In this present study those negatively charged NCs were applied as photosensors for the detection of specific divalent transition metal cations in aqueous solution at the same condition. Consequently, the ZnS:Mn-Cys and ZnS:Mn-Ser NCs showed totally different photosensor activities upon the addition of first-row divalent transition metal ions. The former NCs showed luminescence quenching for most added metal ions except for Zn (II) ions; whereas the latter NCs showed exclusive quenching effect for Cu (II) ions at the same conditions. These results suggested that those NCs can be applied as Zn2+ and Cu2+ ion sensors in water.