Water soluble CdS/ZrO2 core/shell quantum dots (QDs) in aqueous solution were prepared using l-Cysteine and thioglycolic acid (TGA) as capping agents at room temperature using low-cost inorganic salts as precursors. The prepared QDs were characterized by SEM, XRD, FT-IR spectroscopy, UV-Vis absorption, and emission spectroscopy. The fluorescence intensity of CdS/ZrO2 is strongly enhanced by coating with a shell of ZrO2. Such QDs can be used as fluorescent probes for the determination of melamine (MA) by the quenching of QDs. The fluorescence quenching of CdS/ZrO2 core/shell QDs is strongly dependent on the concentration of MA. Therefore, the obvious method for the determination of MA is based on fluorescence, which has favorable merits such as simplicity, rapidity, low cost, and high sensitivity, and it would make it promising for on-site screening of MA adulterant in food products.