Milk fat globule-epidermal growth factor 8 (MFG-E8) is a multifunctional glycoprotein regulating intercellular interactions in various biological and pathological processes. This review summarizes the effects and mechanisms of MFG-E8 in neurodegenerative diseases (NDDs), emphasizing its roles in inflammation, apoptosis, and oxidative stress. In this review, will also explore the potential of MFG-E8 as a diagnostic biomarker and its therapeutic applications in neurodegenerative disorders. Recent studies have revealed intriguing characteristics of using MFG-E8 as a potential drug for treating various brain disorders. While the discovery, origin, expression, and physiological functions of MFG-E8 in various organs and tissues are well defined, its role in the brain remains less understood. This is particularly true for NDDs, indicating unmet medical needs. Elucidating its role in the brain could position MFG-E8 as a potential treatment for NDDs.