Amyloid β-peptide (Aβ) misfolding into β-sheet structures triggers neurotoxicity inducing Alzheimer’s disease (AD). Molecules able to reduce or to impair Aβ aggregation are highly relevant as possible AD treatments since they should protect against Aβ neurotoxicity. We have studied the effects of the interaction of dynorphins, a family of opioid neuropeptides, with Aβ₄₀ the most abundant species of Aβ. Biophysical measurements indicate that Aβ₄₀ interacts with Big Dynorphin (BigDyn), lowering the amount of hydrophobic aggregates, and slowing down the aggregation kinetics. As expected, we found that BigDyn protects against Aβ₄₀ aggregates when studied in human neuroblastoma cells by cell survival assays. The cross-interaction between BigDyn and Aβ₄₀ provides insight into the mechanism of amyloid pathophysiology and may open up new therapy possibilities.