Water-soluble ZnSe quantum dots (QDs) with high luminescence were synthesized by a simple hydrothermal method using selenium powder and zinc acetate solution as precursors, and L-glutathione (GSH) as a stabilizer. In addition, the photoluminescence properties of ZnSe QDs under different conditions (precursor ratios, precursor solution pH, and hydrothermal temperature) were thoroughly investigated. The morphology and structure of as-synthesized ZnSe-GSH QDs under optimized experimental conditions were determined by HRTEM, XRD, and TG-DTA. Results showed that the ZnSe-GSH QDs were tiny nanocrystals with quasi-sphere particles of ∼3 nm size with core-shell structure. The formation and growth mechanism of the core-shell structure were discussed in detail. When the synthesis process was carried out under optimized hydrothermal conditions (reaction temperature, 140 C; reaction time, 45 min; pH value of precursor solution, 10.0; GSH-to-Zn mole ratio, 1.2; and Se-to-Zn mole ratio, 0.2), the as-synthesized ZnSe-GSH QDs emitted blue-purple fluorescence (375 nm) when excited at 321 nm.