Formation of a copper(I) iodide cluster based luminescent metal-organic frameworks (LMOFs) and its utilization for the detection of cysteine (Cys) in aqueous solution are reported. The reaction of bis(amidoquinoline) ligand (L) with copper(I) iodide afforded an LMOF {[(Cu2I2)L2]·2DMSO} n (1) with a 44-sql topology linked by Cu2I2 clusters as a thermodynamic product. Time- and temperature-dependent PXRD experiments confirmed that the entire formation process for 1 is kinetically and thermodynamically controlled. Interestingly, LMOF 1 was also obtained under the mechanochemical condition. Moreover, LMOF 1 dispersed in water shows a selective quenching for Cys over other amino acids due to the strong affinity of Cys to copper(I) iodide. On the basis of the NMR data of L isolated from the decomposition of 1, the decomposition-displacement mechanism was proposed for the sensing of Cys. This result might be utilized for the practical detection of Cys because the sensing material can be prepared simply, and the sensing process is performed in aqueous media.