This chapter evaluates mushrooms’ abilities to produce bioactive substances with therapeutic applications against neurodegenerative diseases. It presents a comprehensive analysis of the existing knowledge about the important molecules in mushrooms, such as polysaccharides, peptides, phenolic compounds, terpenoids, and their antioxidant, anti-inflammatory, and neuroprotective activities. Various mushroom compounds have been tested for activity against significant biological processes such as oxidative stress, neuroinflammation, and neuronal apoptosis. This chapter also highlights various effects mushroom compounds have on relevant signaling cascades, including the Nrf2/ARE and NF-κB pathways. Lastly, this chapter discusses the current preclinical and clinical evidence, along with bioavailability and pharmacokinetic issues and dosages of mushroom-derived compounds. Furthermore, the possibility that mushroom therapies may complement the treatment of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease is further discussed. To summarize, this chapter highlights several knowledge gaps, emphasizing the clinical validation of mushroom-derived compounds along with the critical examination of the specific underlying molecular mechanisms with multidisciplinary approaches related to pharmacology, neuroscience, and molecular biology. The collective investigation of the existing literature suggests that mushrooms have great potential for neurodegenerative disease treatments, which is largely overlooked at present.