Brain deterioration resulting from “protein folding” diseases, such as the Alzheimer's disease (AD), is one of the leading causes of morbidity and mortality in the aging human population. Heat shock proteins (Hsps) constitute the major cellular quality control system for proteins that mitigates the pathological burden of neurotoxic protein fibrils and aggregates. However, the therapeutic effect of Hsps has not been tested in a relevant setting. Here we report the dramatic neuroprotective effect of recombinant human Hsp70 in the bilateral olfactory bulbectomy model (OBX mice) and 5XFAD mouse models of neurodegeneration. We show that intranasally-administered Hsp70 rapidly enters the afflicted brain regions and mitigates multiple AD-like morphological and cognitive abnormalities observed in model animals. In particular, in both cases it normalizes the density of neurons in the hippocampus and cortex which correlates with the diminished accumulation of amyloid-β (Aβ) peptide and, in the case of 5XFAD mice, reduces Aβ plaque formation. Consistently, Hsp70 treatment also protects spatial memory in OBX and 5XFAD mice. These studies demonstrate that exogenous Hsp70 may be a practical therapeutic agent for treatment of neurodegenerative diseases associated with abnormal protein biogenesis and cognitive disturbances, such as AD, for which neuroprotective therapy is urgently needed.