Despite the multidisciplinary integration in the therapeutic management of glioblastoma multiforme (GBM), the prognosis of GBM patients is poor. There is growing recognition that the cells in the tumor microenvironment play a vital role in regulating the progression of glioma. Astrocytes are an important component of the blood-brain barrier (BBB) as well as the tripartite synapse neural network to promote bidirectional communication with neurons under physiological conditions. Emerging evidence shows that tumor-associated reactive astrocytes interact with glioma cells and facilitate the progression, aggression, and survival of tumors by releasing different cytokines. Communication between reactive astrocytes and glioma cells is further promoted through ion channels and ion transporters, which augment the migratory capacity and invasiveness of tumor cells by modifying H⁺ and Ca²⁺ concentrations and stimulating volume changes in the cell. This in part contributes to the loss of epithelial polarization, initiating epithelial-mesenchymal transition. Therefore, this review will summarize the recent findings on the role of reactive astrocytes in the progression of GBM and in the development of treatment-resistant glioma. In addition, the involvement of ion channels and transporters in bridging the interactions between tumor cells and astrocytes and their potential as new therapeutic anti-tumor targets will be discussed.