<p>Glial cells play pivotal roles in homeostatic regulation and driving reactive pathologic changes after nerve injury. Connexins (Cxs) and pannexins (Panxs) have emerged as seminal proteins implicated in cell–cell communication, exerting a profound impact on the response processes of glial cell activation, proliferation, protein synthesis and secretion, as well as apoptosis following nerve injury. These influences are mediated through various forms, including protein monomers, hemichannel (HC), and gap junction (GJ), mainly by regulating intercellular or intracellular signaling pathways. Multiple Cx and Panx isoforms have been detected in central nervous system (CNS) or peripheral nervous system (PNS). Each isoform exhibits distinct cellular and subcellular localization, and the differential regulation and functional roles of various protein isoforms are observed post-injury. The quantitative and functional alterations of the same protein isoform in different studies remain inconsistent, attributable to factors such as the predominant mode of protein polymerization, the specific injury model, and the injury site. Similarly, the same protein isoforms have different roles in regulating the response processes after nerve injury, thus exerting a double-edged sword effect. This review describes the regulatory mechanisms and bidirectional effects of Cxs and Panxs. Additionally, it surveys the current status of research and application of drugs as therapeutic targets for neuropathic injuries. We summarize comprehensive and up-to-date information on these proteins in the glial cell response to nerve injury, providing new perspectives for future mechanistic exploration and development of targeted therapeutic approaches.</p>