Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide. Astrocytes are the largest cell types in the central nervous system (CNS) with numerous functions both physiologically and pathologically. In response to TBI, astrocytes go through a series of alterations referred to as reactive astrogliosis. It is now generally recognized that reactive astrocytes play a dual role in TBI development and tissue repair. Many molecules and signaling pathways have been demonstrated to be involved in the activation of astrocytes, including vital life-supporting substances (such as ATP), regulating hormones (such as gonadal steroids), injury-induced cytokines and chemokines. In this review, we focus on the role of certain specific molecules and related signaling pathways in regulating the activation of astrocytes in TBI. We also discuss the dual role of reactive astrocytes after TBI, which will be critical in the discovery of more appropriate strategies for brain injury treatment.