This study aimed to test the preventive anti-inflammatory properties of Chinese yam polysaccharides (CYP) and sulfated Chinese yam polysaccharides (SCYP) on LPS-induced systemic acute inflammation in mice and investigate their mechanisms of action. The results showed that SCYP can efficiently reduce plasma TNF-α and IL-6 levels, exhibiting an obvious anti-inflammation ability. Moreover, SCYP reduced hepatic TNF-α, IL-6, and IL-1β secretion more effectively than CYP, and significantly altered intestinal oxidative stress levels. In addition, a 16S rRNA gene sequencing analysis showed that CYP regulated the gut microbiota by decreasingDesulfovibrioandSutterellaand increasingPrevotella. SCYP changed the gut microbiota by decreasingDesulfovibrioand increasingCoprococcus, which reversed the microbiota dysbiosis caused by LPS. Linear discriminant analysis (LDA) effect size (LEfSe) revealed that treatment with CYP and SCYP can produce more biomarkers of the gut microbiome that can promote the proliferation of polysaccharide-degrading bacteria and facilitate the intestinal de-utilization of polysaccharides. These results suggest that SCYP can differentially regulate intestinal flora, and that they exhibit anti-inflammatory effects, thus providing a new reference to rationalize the exploitation of sulfated yam polysaccharides.