Ischemic stroke(IS) is the second leading cause of mortality and disability worldwide and neuroimmunity plays an important role in its occurrence and development. The pathogenesis of IS is associated with various metabolic disorders. Yet reports on the amelioration of neuroinflammation by modulating metabolic disorders in clinical practice are scarce. By screening drugs targeting the inflammatory cytokine pro IL-1β in the metabolism-related compound library, we first found that clofibrate, an antihyperlipidemic drug, has an anti-neuroinflammatory effect. However, the role of clofibrate in exerting anti-inflammatory effects in IS and its underlying mechanisms remain unclear. To further investigate the role of clofibrate, we administered clofibrate in an LPS-stimulated microglial cell model and in mice with transient middle cerebral artery occlusion. Notably, clofibrate lowered IL-1β expression, both in vivo and in vitro. Simultaneously, clofibrate reduced infarct volume after ischemia and reperfusion. Moreover, clofibrate affected IS by regulating the expression of NF-κB p65 and NLRP3, thus suppressing the expression of inflammatory factors. These findings suggest that clofibrate could be a prospective medication to alleviate neuroinflammation in IS.