Weanling pigs, with an underdeveloped intestine and immature immune system, are usually subjected to depressed feed intake, growth retardation, and postweaning diarrhea. The aim of this study was to determine 1) the growth response of weaned pigs to supplemental tributyrin (TB) and 2) the potential effects and mechanisms of TB in modulating immune responses of lipopolysaccharide (LPS)-challenged piglets. A total of 240 piglets (Duroc x Large White x Landrace) were weaned at 21 d of age to a control (basal diet), supplemented with antibiotics (AB; + AB), supplemented with TB (+ TB), or with supplemental AB and TB (+ AB+ TB) diets, with 10 replicate pens (6 piglets/pen) per diet. At 49 d of age, male pigs from the control and + TB groups were intraperitoneally injected with LPS (25 mu g/kg BW) or saline (n = 6) and sacrificed at 4 h after injection to collect blood, intestine, and digesta samples for biochemical analysis. There were higher (P < 0.05) feed intake and lower (P < 0.05) percentage of negative growth pig-lets in the + TB groups than in the control group during the first week after weaning. For piglets without LPS challenge, there were higher (P < 0.05) ileal fibroblast growth factor 19 (FGF19) mRNA abundance and total bile acid concentrations in the + TB groups than in the control group, whereas downregulated (P < 0.05) FGF19 expression was observed in the + TB groups after LPS challenge. Lipopolysaccharide challenge in the control group increased (P < 0.05) plasma tumor necrosis factor a and IL-6 concentrations and colonic Escherichia coli amount and decreased (P0.05) observed between + TB groups following LPS challenge. Taken together, dietary supplementation with TB prevented growth retardation through stimulating the appetite of weaned pigs and protected piglets against lethal infection via modulation of inflammatory cytokines production, ileal FGF19 expression, and intestinal acetate fermentation.