Amyloid fibril formation is a critical step in Alzheimer's disease (AD) pathogenesis. Inhibition of Aβ aggregation has shown promising against AD and has been used in clinic trials. Here, a novel strategy is reported for the self-assembly of polyoxometalate–peptide (POM@P) hybrid particles as bifunctional Aβ inhibitors. The two-in-one bifunctional POM@P nanoparticles show an enhanced inhibition effect on amyloid aggregation in mice cerebrospinal fluid. Incorporating a clinically used Aβ fibril-staining dye, congo red (CR), into the hybrid colloidal spheres, the nanoparticles can also act as an effective fluorescent probe to monitor the inhibition process of POM@P via CR fluorescence change in real time. It is believed that such flexible organic–inorganic hybrid systems may prompt the design of new multifunctional materials for AD treatment.