The present study was carried out to evaluate the effect of dietary supplementation of scutellaria baicalensis extract (SBE) on intestinal health in terms of morphology, barrier integrity and immune responses in weaned piglets challenged with E. coli K88. A total of 72 weaned piglets were assigned into two groups to receive a basal diet without including antibiotic additives or the basal diet supplemented 1000 mg SBE /kg diet for 14d. On d 15, 12 healthy piglets from each group were selected to expose to oral administration of either 10 ml 1×109 CFU of E. coli K88 or the vehicle control. After 48 hours of E.coli K88 challenge, blood was sampled, and then all piglets were sacrificed humanly for harvesting jejunal and ileal samples. Dietary supplementation of SBE significantly decreased diarrhea frequency and improved FCR (P < 0.05). SBE supplementation to E.coli K88-challenged piglets improved villous height and VCR (P < 0.05), recovered the protein expression of occludin and ZO-2 in both of the jejunum and ileum (P < 0.05), and mitigated the increases in plasma IL-1β, TNF-α, IL-6, IgA and IgG (P < 0.05). Meanwhile, dietary SBE effectively inhibited the stimulation of NF-κB, P38, and TNF-α as well as IL-1β in the small intestine of piglets challenged by E. coli K88, and prevented the activation of NF-κB/P38 signaling pathways (P < 0.05). Collectively, SBE supplementation can potently attenuate diarrhea in weaning piglets, and decrease inflammatory cytokine expressions may through inhibiting the NF-κB and P38 signaling pathways.