Infection is a major complication of acute stroke and causes increased mortality and morbidity; however, current interventions do not prevent infection and improve clinical outcome in stroke patients. The mechanisms that underlie susceptibility to infection in these patients are unclear. Splenic marginal zone (MZ) B cells are innate-like lymphocytes that provide early defence against bacterial infection. Here we show experimental stroke in mice induces a marked loss of MZ B cells, deficiencies in capturing blood-borne antigen and suppression of circulating IgM. These deficits are accompanied by spontaneous bacterial lung infection. IgM levels are similarly suppressed in stroke patients. β-adrenergic receptor antagonism after experimental stroke prevents loss of splenic MZ B cells, preserves IgM levels, and reduces bacterial burden. These findings suggest that adrenergic-mediated loss of MZ B cells contributes to the infection-prone state after stroke and identify systemic B-cell disruption as a target for therapeutic manipulation.