Grifola frondosa is a widely consumed edible and medicinal fungus, Ancient books record that it can boost qi and fortify the spleen, moisten the lung and protect the liver. Modern people mainly use it to assist in the treatment of diabetes mellitus and various cancers. Over the past three decades, G. frondosa polysaccharides were shown to possess various promising bioactivities, mainly including anti-tumor and immunomodulation, anti-oxidation, anti-hyperglycemia, and meanwhile can effectively act on the skin and hematopoietic stem cells. The purpose of the present review is to provide systematically reorganized information on structural characteristics, biological activities, and structure-activity relationship of G. frondosa polysaccharides to support their further therapeutic potentials and sanitarian functions.