Silicon quantum dots have become attractive nanomaterials due to their excellent biocompatibility and optical performance. However, poor water-solubility greatly limits their wide applications. The paper reported a facile synthesis of imidazole-functionalized silicon quantum dots (termed as IF@SiQDs) via a simple hydrothermal method, in which N-trimethysilylimidazole and sodium citrate were used as the silicon precursor and reducing agent, respectively. The resulted IF@SiQDs exhibits good water-solubility, strong fluorescence with the quantum yield of 30.6% and high photo-stability. More importantly, the competitive coordination of Cu2+ between l-histidine (His) and IF@SiQD creates the unique fluorescence “off-on” response to His. Firstly, Cu2+ was firmly fixed at the surface of IF@SiQD by the coordination bond between Cu2+ and imidazole group to form stable Cum(IF@SiQD)n complex (m>1, n>1). A low concentration of His was introduced to partly replace the IF@SiQD in the complex to produce His-Cu-IF@SiQD, leading to an obvious fluorescence quenching. Based on the fluorescence “off” behaviour, IF@SiQD was developed as a novel optical nanosensor for the detection of His at a low level. Its peak fluorescence intensity linearly decreases with the increase the concentration of His in the range of 1.6×10−6–2×10−4M with the detection limit of 5.2×10−7M. Further, the His-Cu-IF@SiQD can be changed into non-fluorescent Cu(His)2 complex in the presence of a high concentration of His, accompanying the release of free IF@SiQDs and increase in the fluorescence intensity. Based on the fluorescence “on” behaviour, IF@SiQDs was used for the optical detection of His at a high level. Its peak fluorescence intensity linearly increases with the increase the concentration of His in the range of 2.8–5×10−3M with the detection limit of 2.2×10−3M. The as-proposed method provides the advantage of sensitivity, selectivity and linear range, it has been successfully applied in the fluorescent detection of His in human urine and in medical amino acid injection. The study also opens an avenue for the design of various functional silicon quantum dots that hold the great promise in the potential applications such as nanosensors, biocatalyst and cell imaging.