Systemic immunosuppression has been associated with stroke for many years, but the underlying mechanisms are poorly understood. In this study, we demonstrated that stroke induced profound behavioral changes in hepatic invariant NKT (iNKT) cells in mice. Unexpectedly, these effects were mediated by a noradrenergic neurotransmitter rather than a CD1d ligand or other well-characterized danger signals. Blockade of this innervation was protective in wild-type mice after stroke but had no effect in mice deficient in iNKT cells. Selective immunomodulation of iNKT cells with a specific activator (α-galactosylceramide) promoted proinflammatory cytokine production and prevented infections after stroke. Our results therefore identify a molecular mechanism that leads to immunosuppression after stroke and suggest an attractive potential therapeutic alternative to antibiotics, namely, immunomodulation of iNKT cells to prevent stroke-associated infections.