Atherosclerosis, the leading cause of cardiovascular disease, poses a great threat to human health. Chinese yam polysaccharides (CYPs) possess various pharmacological effects and biological activities. However, the anti-atherosclerotic effects of CYPs and their underlying mechanisms remain unclear. Here, we explored whether CYPs could regulate the diversity and composition of the gut microbiome, as well as alleviate high-fat-diet (HFD)-induced atherosclerosis. In the present study, the atherosclerotic pathology, serum parameters, and gut microbiota analyses were used to determine how CYPs alleviate atherosclerosis in HFD-fed ApoE^−/− mice. The animal study protocol was approved by the Committee on the Ethics of Animal Experiments of China Agricultural University (Approval Code: AW92503202-5-1; Approval Date: 29 May 2023). Our results indicated that CYP treatment (400 mg/kg/day) for 6 weeks in ApoE-/- mice (n=12 mice in both control and CYP groups) reduced the plaque size to 50%, reduced the lipid and necrotic areas to 60%, and stabilized the atherosclerotic plaques. Concomitantly, CYPs slightly reduced the levels of TG and LDL-C in serum, while they elevated the HDL-C level. CYPs also decreased the serum MDA level (to 70%) while increasing the levels of GSH, SOD, and GSH-PX (to 120%). Further investigations demonstrated that CYPs reduced the expression of chemotactic factor Mcp-1 (to 20%) and the expression of pro-inflammatory cytokines (Tnf-α, Il-1β, Il-6, and Nos2, 20% to 75%) in aortas. Remarkably, CYP supplementation produced structural changes in the gut microbiota, reducing the abundance of Firmicutes and Actinobacteriota and increasing the Bacteroidota and Proteobacteria at the phylum level. Collectively, CYPs can exert hypolipidemic, anti-oxidant, anti-inflammatory, and gut microbiota regulation effects, ultimately inhibiting atherosclerosis progression, and they could be further exploited as potential anti-atherosclerosis bioactive nutrients.