Natural plant polysaccharides are renowned for their broad spectrum of biological activities, making them invaluable in both the pharmaceutical and food industries. Their safety, characterized by low toxicity and minimal side effects, coupled with their potential therapeutic properties, positions them as crucial elements in health-related applications. The functional effectiveness of these polysaccharides is deeply connected to their structural attributes, including molecular weight, monosaccharide components, and types of glycosidic bonds. These structural elements influence how polysaccharides interact with the gut microbiota, potentially alleviating various metabolic and inflammatory disorders such as inflammatory bowel disease, diabetes, liver-associated pathologies, obesity, and kidney diseases. The polysaccharides operate through a range of biological mechanisms. They enhance the formation of short-chain fatty acids, which are pivotal in keeping intestinal health and metabolic balance. Additionally, they strengthen the intestinal mucosal barrier, crucial for deterring the ingress of pathogens and toxins into the host system. By modulating the immune responses within the gut, they help in managing immune-mediated disorders, and their role in activating specific cellular signaling pathways further underscores their therapeutic potential. The review delves into the intricate structure–activity relationships of various natural polysaccharides and their interactions with the intestinal flora. By understanding these relationships, the scientific community can develop targeted strategies for the use of polysaccharides in therapeutics, potentially leading to innovative treatments for a range of diseases. Furthermore, the insights gained can drive the advancement of research in natural polysaccharide applications, providing direction for novel dietary supplements and functional foods designed to support gut health and overall well-being.