The present study aimed to investigate the effects of steam-exploded Dictyophora indusiata polysaccharide (DIPS) on lipopolysaccharide (LPS)-induced inflammation of mice. The results showed that DIPS significantly improved colonic shortening by LPS-induced inflammation, and the mRNA expression of Occludin (Occ) and Zonula occludens-1 (ZO-1) in colon tissues was increased 9.86- and 2.69-fold after DIPS intervention, respectively. In addition, DAI scores decreased from 1.15 to 0.74, while the mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were also reduced by DIPS intervention. It is remarkable that DIPS modulated the composition of gut microbiota and enhanced the relative abundance of Bifidobacterium, unclassified_o_Oscillospirales and Faecalibaculum. Furthermore, the levels of acetic acid and propionic acid of the gut contents in mice were restored to (0.94 ± 0.24) mg/g and (0.23 ± 0.10) mg/g after the intervention of DIPS, which was 3.03- and 2.56-fold of the LPS group, respectively. In conclusion, DIPS protected against LPS-induced inflammation, which provides new insights into the anti-inflammatory effect of edible fungi polysaccharide.