In this study, the potential effects of a novel alkali-soluble polysaccharide (ASPP) from purple sweet potato on colonic histopathology, inflammation and microbiota composition in dextran sulfate sodium (DSS)-induced colitis mice were evaluated. The results indicated that ASPP restored the immune organ indices, increased colon length, improved colonic histopathology in colitis mice as well as inhibited the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in colonic tissue and serum. Moreover, 16S rRNA phylogenetic sequencing revealed that ASPP ameliorated the compositions and functions of gut microbiota in DSS-induced colitis mice. It was found that Parasutterella, Desulfovibrio, Lachnospiraceae, Lactobacillus, Erysipelotrichaceae, Bacteroidetes were the key bacteria associated with ulcerative colitis (UC). Taken together, ASPP alleviated colonic inflammation via blocking pro-inflammatory cytokines; meanwhile ASPP could modulate the structure of gut microbiota in DSS-induced colitis mice.