Cadmium (Cd), as Group I carcinogen, can induce damage to various organs including the gut. It is of great importance to meet the rising demand for effective therapies against Cd-induced damage and investigate the mechanism. Flammulina velutipes is a popular edible mushroom, despite the well-known health benefits of Flammulina velutipes, little is known about the effect of its polysaccharide (FVP) against CdCl2-intestinal injury. In this study, a FVP (uronic acid, 5.10 %; degree of methylation, 41.24 %) was produced via hot water extraction (85 °C) and ethanol precipitation. The FVP contained eight major monosaccharides and exhibited good thermal stability at temperatures lower than 139.73 °C. FVP (100 mg/kg b. w., gavage for 4 weeks) alleviated CdCl2 (1.5 mg/kg b. w., gavage for 4 weeks)-induced intestinal inflammation and apoptosis, intestinal permeability alteration and intestinal barrier disruption. FVP increased the abundance of Bacteroides, whilst decreasing the abundance of Desulfovibrionales and Clostridium. FVP also restored the levels of short-chain fatty acids (SCFAs), including acetic, propionic, isobutyric, butyric, isovaleric and valeric acids. Correlation analysis indicated the interplays among the FVP, gut microbes, SCFAs, intestinal barrier/cells and gut inflammation. FVP enhances the metabolic functions of gut microbiota via functional pathways analyzed by KEGG database. Furthermore, gut microbial transplantation of FVP + CdCl2 group mice partially alleviated CdCl2 caused-gut damage. Thus, FVP may be an effective therapeutic agent against CdCl2-induced gut damage via SCFA-mediated regulation of intestinal inflammation and gut microbiota-related energy metabolism. This study may open a new avenue for developing alternative strategies to prevent CdCl2-caused injury.