Significance Heat shock protein 70 (Hsp70) is a critical protein with many protective activities inside the cell. We demonstrate that forced secretion of Hsp70 is beneficial against the extracellular protein aggregates typical of Alzheimer’s disease (AD). Engineering Hsp70 enables its interaction with the amyloid-β42 peptide, the main pathogenic agent in AD. This interaction suppresses amyloid-β toxicity in the eye, reduces cell death in brain neurons, and protects neuronal architecture and function. Interestingly, secreted Hsp70 exerts this protective activity without utilizing its refolding activity and without decreasing the levels and aggregation of amyloid-β42. These results suggest a protective mechanism mediated by direct binding to amyloid-β42, which blocks amyloid-β42 neurotoxicity. We discuss here the potential therapeutic benefits of secreted Hsp70.