Interleukin-18 (IL-18), a pro-inflammatory cytokine, is thought to be associated with inflammation in many neurological diseases such as ischemic stroke and poststroke depression, but the role of IL-18 in inflammatory injury after intracerebral hemorrhage (ICH) remains unclear. In this study, we established the ICH model in male mice and found that IL-18 expression including protein and mRNA levels was significantly increased in brain tissues after ICH. Meanwhile, exogenous IL-18 exacerbated cerebral hematoma and neurological deficits following ICH. In the IL-18 knockout group, the size of hematoma and neurological functions after ICH was decreased compared with the wild-type group, suggesting the critical role of IL-18 on the modulation of brain injury after ICH. Importantly, exogenous IL-18 increased microglial activation in brain tissues after ICH. Furthermore, IL-18 knockout resulted in the reduction of activated microglia after ICH. These results indicated that IL-18 may regulate the inflammatory response after ICH through the activation of microglia. Thus, IL-18 is expected to be a promising therapeutic target for secondary brain injury after ICH.