Colitis has become a public health problem in recent years due to its high incidence rate. The extracellular polysaccharides produced by microorganisms were reported to possess the ability to alleviate colitis. A mannan (HPA) was isolated from the fermented broth of the marine fungus Hansfordia sinuosae, and its effect on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) was investigated in vivo. The results showed that HPA could relieve the disease symptoms and colon pathological injury of UC mice. Further mechanism analysis indicated that HPA repressed the level of NLRP3 inflammasome and inflammatory mediators TNF-α and IL-1β, and promoted the production of IL-10. HPA repaired the colonic barrier by increasing the expression of tight junction proteins ZO-1 and occludin, as well as the number of goblet cells. It also restored the imbalance of the gut microbiota caused by DSS treatment by enhancing the abundance of beneficial bacteria such as Clostridia UCG-014 and Bifidobacterium, while reducing the abundance of potentially harmful bacteria like Escherichia-Shigella and Enterococcus. Besides, HPA relieved the depression-like behavior of UC mice by inhibiting inflammatory response and activation of astrocyte and microglia in brain tissues. In short, HPA had the potential to be developed as functional foods or drugs for the treatment of colitis and accompanied depression-like behavior.