Neurodegenerative diseases (NDs) are a widespread and serious global public health burden, particularly among the older population. At present, effective therapies do not exist, despite the increasing understanding of the different mechanisms of NDs. In recent years, some drugs, such as galantamine, entacapone, riluzole, and edaravone, have been proposed for the treatment of different NDs; however, they mainly concentrate on symptom management and confer undesirable side effects and adverse reactions. Therefore, there is an urgent need to find novel drugs with fewer disadvantages and higher efficacy for the treatment of NDs. Mushroom polysaccharides are macromolecular complexes with multi-targeting bioactivities, low toxicity, and high safety. Some have been demonstrated to exhibit neuroprotective effects via their antioxidant, anti-amyloidogenic, anti-neuroinflammatory, anticholinesterase, anti-apoptotic, and anti-neurotoxicity activities, which have potential in the treatment of NDs. This review focuses on the different processes involved in ND development and progression, highlighting the neuroprotective activities and potential role of mushroom polysaccharides and summarizing the limitations and future perspectives of mushroom polysaccharides in the prevention and treatment of NDs.