Parkinson's disease (PD) is a progressive neurodegenerative disorder, pathologically characterized by abnormal alpha-synuclein aggregation and Lewy body formation, which leads to neurodegeneration and dopaminergic cell death. Currently there is no cure for PD. Thus, it is imperative to develop a new therapeutic approach. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a member of unconventional evolutionary conserved protein families. It has unique molecular structure and capable to detect and rescue apoptotic neurons. MANF protein could selectively enhance the survival and sprouting of nigral dopaminergic neurons in vitro. Studies have shown that MANF can protect and repair dopaminergic neurons in animal models of PD. MANF is localized in the endoplasmic reticulum (ER) lumen function in regulation of ER stress and unfolded protein responses. Its C terminal domain is complete homologous to SAP domain of Ku70, which functions in anti-apoptosis. In this review, we described molecular structure, tissue expression of MANF, and summarized preclinical studies using MANF for PD therapy. We also discussed the mechanisms of MANF for the treatment of PD.