Molecular chaperones (heat-shock proteins [Hsps]) and co-chaperones are proteins that sustain intracellular homeostasis through folding and unfolding of proteins. This referred to highly conserved protein quality control system that are involved in sorting and processing of newly synthesized, mis localized, and misfolded proteins. Chaperones play an important role in the entire life span of a particular protein; first, it helps the nascent polypeptide chain to fold to its native state, there after checks the misfolded/metastable intermediates, disaggregates the aggregated proteins, and then finally removes the terminally aggregated proteins via proteolytic degradation. Dysfunction in chaperone-mediated proteostasis has been detected in numerous neurodegenerative diseases (NDDs), like Parkinson’s (PD), Huntington’s (HD), and Alzheimer’s (AD). Molecular chaperones and their co-chaperones are involved in a vital part in synaptic proteostasis by promoting protein folding, preventing misfolding, and regulating protein degradation. This review explores the mechanisms by which chaperones and co-chaperones maintain synaptic proteostasis, their role in neurodegenerative disease, and potential therapeutic strategies for targeting chaperone-mediated proteostasis to prevent or treat neurodegeneration. By understanding the importance of chaperone-mediated proteostasis for maintaining neuronal health, we may uncover new avenues for the prevention and treatment of neurodegenerative diseases.