Post-stroke depression (PSD) is a common and serious complication that affecting one third of stroke patients for poor quality of life, high mortality, high recurrent rate, and slow recovery. Recent studies showed that serum interleukin-18 (IL-18) level is a biomarker for patients with PSD. However, the role of IL-18 in the pathology of PSD is still unclear. In this study, we demonstrate that in IL-18 level in the ischemic brain significantly increased in mice with depression-like behaviors that caused by the combined use of chronic spatial restraint stress and middle cerebral artery occlusion. Interestingly, IL-18 expression was mainly found in neurons at early phase and in microglia in late phase. Injection of exogenous IL-18 in to the amygdala, but not the hippocampus or the striatum, caused severe depression-like behaviors. On the contrary, the blockage of endogenous IL-18 by IL-18 binding protein, a specific antagonist of IL-18, rescued depressive phenotypes in SIR mice. IL-18 KO mice exhibited the resistance to spatial restraint stress and cerebral ischemia injury. Finally, we found that IL-18 mediated depressive behaviors by the interaction of IL-18 receptor and NKCC1, a sodium-potassium-chloride co-transporter that is related to GABAergic inhibition. Administration of NKCC1 antagonist bumetanide exerted a therapeutic effect on the in IL-18-induced depressive mice. Therefore, we demonstrate that increased IL-18 in the brain caused depression-like behaviors by promoting the IL-18 receptor/NKCC1 signaling pathway. Targeting IL-18 and its downstream pathway is a promising strategy for the prevention and treatment of PSD.