The neurotrophic factor, Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), promotes neuronal health and survival. MANF is conserved in metazoans and necessary for the protection of dopaminergic neurons. The neuroprotective role of MANF involves regulation of the ER unfolded protein response (ER-UPR). Recent work has shown that MANF also functions in many other tissues and affects autophagy genes. Previously, we reported thatC. elegans manf-1mutants show defects including increased ER stress, α-Synuclein aggregation, and age-dependent dopaminergic neurodegeneration. In this study, we have further investigated manf-1’s function and describe its mechanism of action in regulating stress response, protein aggregation and aging. Our results showed that exposure to ER stress-inducing agents causedmanf-1transcription and protein expression to be upregulated. Consistent with the protective role ofmanf-1, mutant animals showed greater sensitivity to ER stress and died prematurely. We generatedmanf-1p::manf-1::mCherry(MANF-1OE) andhsp::manf-1transgenic strains overexpressing MANF and found that these animals had an extended lifespan, reduced protein aggregation, and increased neuronal health. Thein vivoanalysis of MANF-1 expression revealed that the protein was secreted and present in many tissues. Subcellular studies showed that MANF-1 was localized to lysosomes. We also observed that MANF-1OEworms had reduced LGG-1 and SQST-1/p62 levels, and increased expression and nuclear localization of the autophagy transcription factorhlh-30/TFEB. Thus, MANF-1 regulates protein homeostasis through increased lysosome activity and autophagic flux. Collectively, our work provides a novel understanding of MANF-1 function in promoting neuronal health, stress response, proteostasis, and lifespan of animals.