Astrocytic dysfunctions have increasingly been recognized as a significant element in epilepsy pathophysiology. The prominent expression of connexin channels is one of the key features of astrocytes, essential for their extensive intercellular coupling. It is currently debated whether astrocytic connexins have pro- or anti-epileptic effects. The existence of two types of connexins, namely Cx30 and Cx43, which display different properties as well as several functions beyond gap junction formation, such as hemichannel constituents or signaling elements, further makes it more complex to investigate the specific contribution of each astroglial connexin and associated functions to epilepsy. In our work, we used the kainate mouse model of temporal lobe epilepsy as well as human postoperative cortical tissues from epileptic patients to address these questions. We first found that each connexin is differentially regulated by seizures in kainate mice. Further, we observed that the two astroglial connexins differentially contribute to the epileptic phenotype: while Cx30 mediates the kainate-induced decrease in astroglial coupling, Cx43 hemichannels are specifically activated during the chronic phase of epilepsy. We also observed that Cx43, but not Cx30, contributes to seizure generation and their accompanying characteristic neuroanatomical features, such as granule cell dispersion and cell loss in the dentate gyrus, and astrogliosis. Finally, we showed that the Cx43 hemichannel activity is responsible for this observed effect in kainate mice and human postoperative epileptic tissues. Altogether, our study provides new molecular and functional insights into the role of astroglial connexins in chronic epilepsy in mice and humans.