<p>Mangiferin, a polyphenol of natural occurrence predominantly present in <i>Mangifera indica</i>, has attracted significant interest because of its multiplicity of pharmacological activities, of which its neuroprotective activity is of particular interest. Herein, the review delves into the biosynthetic mechanisms, structural properties, and action mechanisms responsible for the therapeutic value of mangiferin in neurological disorders. Of special note is that mangiferin has antioxidative, anti-inflammatory, and anti-apoptotic activities, which are responsible for its effectiveness in reducing cognitive impairments and neuronal damage in disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, stroke, epilepsy, depression, anxiety, and general cognitive decline. Though being of low bioavailability, more recent approaches such as chemical derivatization, nanoparticle-mediated drug delivery, and intranasal delivery have the promise to enhance its central nervous system (CNS) delivery. By combining preclinical and mechanistic studies, the review herein highlights the potential of mangiferin as a multitherapeutic neuroprotectant and addresses new approaches to facilitate its clinical application.</p>