Post-stroke inflammation may contribute to secondary brain injury and systemic immunosuppression. Interleukin(IL)-37 is an immunosuppressive cytokine belonging to the IL-1 superfamily with no mouse homologue yet identified, the effects of which have not been studied in stroke. Here we report: (1) the effect of ischemic stroke on circulating IL-37 in humans; and (2) the effect of IL-37 on stroke outcome measures in mice transgenic for human IL-37 (IL-37tg). We found that in the first 3 days after ischemic stroke in 55 patients, the plasma abundance of IL-37 was ~2-fold higher than in 24 controls. In IL-37tg mice, cerebral ischemia-reperfusion resulted in marked increases in plasma IL-37 (~9-fold) and brain IL-37 mRNA (~7,000-fold) at 24 h compared with sham-operated IL-37tg mice. Further, compared with wild-type (WT) mice subjected to cerebral ischemia-reperfusion, IL-37tg mice exhibited less severe locomotor deficit, smaller cerebral infarcts and reduced bacterial lung infection. In the ischemic hemisphere, there were 60% fewer pro-inflammatory microglia-macrophages and up to 4-fold higher expression of anti-inflammatory markers in IL-37tg compared to WT mice. Our data show that IL-37 expression is increased following ischemic stroke in humans and IL-37tg mice, and may exert protective effects by modulating post-stroke inflammation in the brain and periphery.