Glial Fibrillary Acidic Protein (GFAP) is regarded as a marker of reactive astrogliosis. Recent studies have demonstrated that signal transducer and activator of transcription-3, STAT3 regulates GFAP expression after brain injuries. However, whether STAT3 controls astrogliosis in epilepsy is not clear. In this study, we measured p-STAT3 and GFAP expression during the epileptic process using immunohistochemistry, Western blotting and immunofluorescence. Both p-STAT3 and GFAP expression were highly expressed in the rat hippocampus during different phases of the epileptic process. The augmentation of GFAP expression was inhibited by AG490, a janus kinase 2 (JAK2, an upstream gene of STAT3) inhibitor. The coexpression of p-STAT3 and GFAP was detected in the epileptic rat hippocampus and temporal neocortex of patients. These findings indicate that epilepsy involves the activation of STAT3 that up-regulates the expression of GFAP, which may play an important role in epileptogenesis.