Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling the metabolic dysfunction that is associated with chronic inflammation remains unexplored. We demonstrate here that administration of lacto-N-fucopentaose III (LNFPIII), a Lewis(X)-containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased interleukin-10 (Il-10) production by LNFPIII-activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment upregulates nuclear receptor subfamily 1, group H, member 4 (Fxr-α, also known as Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-activator protein 1 (Ap1) pathway seems to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide new therapeutic approaches to treat metabolic diseases.