Edible and medicinal mushroom polysaccharides (EMMPs) have been widely studied for their various biological activities. It has been shown that EMMPs could modulate microbiota in the large intestine and improve intestinal health. However, the role of EMMPs in protecting the gastric barrier, regulating gastric microbiota, and improving gastric health cannot be ignored. Hence, this review will elucidate the effect of EMMPs on gastric and intestinal barriers, with emphasis on the interaction of EMMPs with microbiota in maintaining overall gastrointestinal health. Additionally, this review highlights the gastroprotective effects and underlying mechanisms of EMMPs against gastric mucosa injury, gastritis, gastric ulcer, and gastric cancer. Furthermore, the effects of EMMPs on intestinal diseases, including inflammatory bowel disease, colorectal cancer, and intestinal infection, are also summarized. This review will also discuss the future perspective and challenges in the use of EMMPs as a dietary supplement or a nutraceutical in preventing and treating gastrointestinal diseases.