Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-β (Aβ) peptides into β-sheet-rich oligomers and insoluble amyloid fibrils. Experimental studies reported that 1,2-(dimethoxymethano)fullerene (DMF), a water-soluble fullerene derivative, inhibits strongly Aβ peptide aggregation at the early stage. However, the interaction and binding mechanisms are not well understood. In this study, we have investigated the detailed interaction of a DMF molecule with a fibrillar hexamer of full-length Aβ42 and the resulting structural alterations by performing multiple all-atom explicit solvent molecular dynamics (MD) simulations. Starting from different initial states with a minimum distance of 2 nm between the DMF and the Aβ protofibril, our MD simulations show that the DMF binds to the Aβ protofibril via both slow and fast binding processes. Three dominant binding sites are identified: the central hydrophobic core (CHC) site (17LVFFA21), the turn site (27NKGAI31), and the C-terminal β-sheet site consisting of the smallest side-chain residue glycine and hydrophobic residues (31IIGLMVGGVVI41). Binding energy analyses reveal the importance of π-stacking interactions, especially in the CHC site, hydrophobic interactions, and curvature matching. Strikingly, we find that the binding of DMF to the turn region can disrupt the D23-K28 salt-bridge that is important for the Aβ fibrillation. These results provide molecular insight into the binding mechanism of fullerene to Aβ protofibrils and offer new routes for the therapeutic drug design using fullerene derivatives against AD.