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Polygonatum polysaccharides are the major active components of the traditional Chinese medicinal herb Polygonatum. They exhibit marked structural heterogeneity with diverse glycan types and possess a broad spectrum of biological activities, including anti-inflammatory, immunomodulatory, antioxidant, and glucose-lipid metabolic regulatory effects. These properties have made them a research hotspot in the fields of medicine and health. Modern pharmacological studies have shown that Polygonatum polysaccharides can modulate multiple biological targets by regulating several signaling pathways, such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). Through these pathways, they influence inflammatory cytokine release, immune cell activation, oxidative stress responses, and glucose-lipid metabolism, thereby exerting synergistic multi-target and multi-pathway effects. This enables their promising application in the prevention and treatment of inflammatory diseases, metabolic disorders, cancers, and other conditions. Although numerous in vivo and in vitro studies have validated the wide-ranging biological activities of Polygonatum polysaccharides, challenges remain in their clinical translation. Future research should focus on the precise elucidation of structure-activity relationships, characterization of metabolic processes in vivo, and acquisition of rigorous evidence from clinical research to support the translation of Polygonatum polysaccharides from basic research to clinical application.