This study evaluated the effects of dietary coated sodium butyrate (CSB) on lipopolysaccharide (LPS)-induced inflammatory response in weaned lambs. A basal diet was supplemented with CSB at 0, 2 or 3 g/kg feed for 28 days and/or intraperitoneally injected with 100 lg/kg BW Escherichia coli LPS (0 g/kg CSB, 0 g/kg CSB and LPS, 2 g/kg CSB and LPS, 3 g/kg CSB and LPS). The results showed that CSB supplementation conferred significant protective effects against LPS-induced inflammatory response by reducing in the levels of D-lactate (DLA), diamine oxidase (DAO), inflammatory cytokines (TNF-a, IL-1b and IL-8) in the serum and upregulated expression of tight junction proteins (claudin-3, ZO-1 and occludin) in the ileum. Meanwhile, CSB pre-treatment significantly suppressed LPS-induced TLR4/NF-jB signalling pathway mRNA expression (MyD88, TLR4, NF-jB, IL-6 and IL-1b) and down-regulated TLR4/NF-jB signalling pathway protein expression (MyD88, TLR4, NF-jB p65 and p-NF-jB p65). Furthermore, dietary CSB supplementation improved intestinal morphology. Lastly, bacterial 16S rRNA gene sequencing indicated that CSB could alter intestinal microbiota composition at genus levels. Taken together, our results indicate CSB could maintain intestinal health, improve intestinal morphology, modulate the microbial community and decrease LPS-induced inflammatory response in lambs.