Intestinal barrier inflammatory damage is commonly accompanied by hypoxia. The hypothesis that dietary Acanthopanax senticosus polysaccharides (ASPS) might modulate HIF-1α signaling pathway and contribute to attenuate intestinal injury was tested in lipopolysaccharide (LPS)-challenged piglets. Thirty-six weaned pigs were randomly allocated to one of the following three groups: (1) basal diet+saline challenge; (2) basal diet+LPS challenge; (3) basal diet with 800 mg/kg ASPS+LPS challenge. LPS was injected at 15, 18 and 21 d, and intestinal sections were sampled following blood collection at 21 d of the trial. The results showed ASPS administration reversed (P＜0.05) LPS-induced decrease in average daily feed intake and rise (P＜0.05) of diarrhea incidence and index. Biochemical index reflecting gut barrier damage and function involving ileal pro-inflammatory cytokines (TNF-α and IL-1β) and enzymes activity (DAO and lactase), as well as circulatory D-xylose were normalized (P＜0.05) in LPS-challenged piglets receiving ASPS. ASPS also ameliorated intestinal morphological deterioration of LPS-challenged piglets, proven by elevated ileal villus height (P＜0.05) and improved appearance of epithelial villus and tight junction ultrastructure. Moreover, ASPS prevented LPS-induced amplification of inflammatory mediators, achieved by depressed mRNA abundance of TNF-α, iNOS, and concentration of IL-1β in ileum. Importantly, ileal protein expressions of HIF-1α, COX-2 and NFκB p65 were also suppressed with ASPS administration (P＜0.05). Collectively, these results suggest that the improvement of mucosal inflammatory damage and diarrhea in immune stress piglets are possibly associated with a novel finding where HIF-1α/COX-2 pathway down-regulation involved in NFκB p65-inducible releasing of inflammatory cytokines by dietary ASPS.