Ischemic stroke is a frequent cause of mortality and disability, and astrocyte reactivity is closely associated with injury outcomes. Fibroblast growth factor 21 (FGF21), an endogenous regulator, has been shown to perform pleiotropic functions in central nervous system (CNS) disorders. However, studies on neurological diseases have paid little attention to the effects and detailed mechanisms of FGF21 in astrocytes. Here, we found elevated serum levels of FGF21 in stroke patients and transient middle cerebral artery occlusion (tMCAO) mice. In the peri-infarct cortex, microglia and astrocytes serve as sources of FGF21 in addition to neurons. MRI and neurobehavioral assessments of wild-type (WT) and FGF21