An attractive strategy to contrast the Alzheimer disease (AD) is represented by the development of β-sheet breaker peptides (BSB). β-sheet breakers constitute a class of compounds which have shown a good efficacy in preventing the Aβ fibrillogenesis; however, their mechanism of action has not been precisely understood. In this context, we have studied the structural basis underlying the inhibitory effect of Aβ(1-42) fibrillogenesis explicated by two promising trehalose-conjugated BSB peptides using an all-atom molecular dynamics (MD) approach. Our simulations suggest that the binding on the two protofibril ends occurs through different binding modes. In particular, binding on the odd edge (chain A) is guided by a well defined hydrophobic cleft, which is common to both ligands. Moreover, targeting chain A entails a significant structure destabilization leading to a partial loss of β structure and is an energetically favoured process. A significant contribution of the trehalose moiety to the stability of the complexes emerged from our results. The energetically favoured hydrophobic cleft detected on chain A could represent a good starting point for the design of new molecules with improved anti-aggregating features.