Inflammation significantly influences the development of gastrointestinal (GI) diseases such as inflammatory bowel diseases (IBD)and ulcerative colitis, which disrupts normal digestive functions, leading to tissue damage and various symptoms. This research explores the preventive effects of quinoa polysaccharides (QPS) on lipopolysaccharide (LPS)-induced systemic acute inflammation in mice and their mechanism of action. The findings revealed that QPS alleviated LPS-induced inflammation symptoms, enhanced the mice behavior score and their immune organ index, reduced pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) levels, elevated the expression level of tight junction proteins (ZO-1, MUC2). Additionally, the levels of superoxide dismutase (SOD), malondialdehyde (MDA) and total antioxidant capacity (T-AOC) were improved via QPS administration. Further, our research suggested that QPS enhanced the diversity and abundance of gut microbiota compared to that of LPS mice, leading to an increase in the short-chain fatty acids in mice feces. Linear discriminant analysis (LDA) effect size (LEfSe) showed that QPS administration could lead to a range of gut biomarkers, promoting the enhancement of polysaccharide-metabolizing bacteria. The results of 16S rRNA sequencing indicated that QPS alleviates LPS-induced inflammation by enhancing the richness of beneficial bacteria such as Bacteroides and Lactobacillus. Linear discriminant analysis (LDA) effect size (LEfSe) showed that QPS administration could lead to a range of gut biomarkers, promoting the enhancement of polysaccharide-metabolizing bacteria. UPLC Q-TOF-MS was performed to analyze metabolites in the fecal samples. LPS administration significantly altered metabolite levels detected in mice feces in which some metabolites have decreased such as xanthosine and hypoxanthine while an increase in some metabolites in mice that received QPS, metabolomics analysis showed the beneficial effects of QPS primarily mediated via amino and bile acid-related metabolism pathways. Our research could offer the basis for further studies and applications of quinoa polysaccharides.