The discovery of nutritious dietary supplements and side effect-free therapeutics are a priority in the current scenario of increasing instances of metabolic syndromes. In this direction, mushroom polysaccharides have shown immense promise. Scores of studies have characterized and evaluated their biological relevance, which range from antioxidant, anti-inflammatory, anticancer, antidiabetic, antimicrobial, and antilipemic to immunomodulatory. Hence, it is important to accumulate the key findings of these investigations, and to apply the insights to develop functional foods, and immunomodulators. This review attempts to meet this goal by gleaning the key discoveries on mushroom polysaccharides in the recent years, and to present them in a comprehensive manner. With this objective, the physiological relevance of the polysaccharides, the underlying mechanism, and hurdles in the path of their therapeutics transition, have been discussed. Finally, critical comments have been made to expedite research in this area.