We here report a facile pH-guided strategy for the fabrication of water-soluble protein/copper nanoclusters (CuNCs) hybrid nanostructures with stable and bright luminescence resulted from aggregation-induced emission. Using l-cysteine as both the reducing and capping agents, the synthesized CuNCs showed a good reversible pH-responsive aggregation and dispersion in the solution. The CuNCs formed insoluble macroscopic aggregates with stable red-colored emission (620 nm) at pH 3.0 but became soluble with weak luminescence at pH <1.5 or pH >4.0. The highly reversible pH-responsive properties of the CuNCs made it feasible to achieve water-soluble protein/CuNCs hybrid nanostructures in the presence of protein without any external forces (e.g., sonication). The weak luminescent CuNCs were first mixed with protein under neutral condition (e.g., pH 7.0), followed by tuning of the pH to acidic conditions (e.g., pH 3.0) to form luminescent protein/CuNCs hybrid nanostructures, the sizes of which were much smaller than those of the protein-free macroscopic CuNC aggregates. This strategy was easily applicable to other dispersing agents (e.g., glucose oxidase), opening a new pathway for the construction of many other smart water-soluble luminescent biomolecule/nanocluster hybrid nanostructures with various applications.