Three major polysaccharides (wHEP-1, wHEP-2, and wHEP-3) were isolated from the mycelium of Hericium erinaceus. This study assessed their chemical and physical properties, molecular weight, monosaccharide compositions, and anti-ulcerative colitis ability to protect Caco-2 cells from lipopolysaccharide (LPS)-induced inflammation. The results showed that the average molecular weight of wHEP-1, wHEP-2, and wHEP-3 was 5010, 1812, and 1118 Da, respectively. wHEP-1 was composed of mannose, glucose, and galactose in a molar ratio of 1.2:16.9:1:1, whereas wHEP-2 and wHEP-3 were composed of glucose and galactose in different molar ratios. Anti-inflammatory activity was compared using LPS-induced Caco-2 cells and a rat model. wHEP-1 exhibited the best anti-inflammatory activity. Thus, the polysaccharide from H. erinaceus as a natural material shows potential for the development of alternative therapies.