Aquaporin-4 (AQP-4) is an aquaporin composed of six helical transmembrane domains and two highly conserved ASN-pro-ALA (NPA) motifs. It is strongly expressed in rodent and human spinal cord tissues and plays a key role in the pathological process after SCI. After SCI, edema, glial scarring, and inflammation can accelerate the progression of injury and lead to deterioration of function. Many studies have reported that AQP-4 plays an important role in SCI. In particular, it plays an important role in secondary pathological processes (spinal cord edema, glial scar formation, and inflammatory response) after SCI. Loss of AQP-4 has been associated with reduced spinal edema and improved prognosis after SCI in mice. In addition, downregulation of AQP-4 reduces glial scar formation and the inflammatory response after SCI. There is a consensus from numerous studies that AQP-4 may be a potential target for SCI therapy, which guides the ongoing investigation for molecular therapy of SCI. Here, we review the structure of AQP-4, its expression in normal and damaged spinal cord, and its role in SCI, as well as discuss the theoretical basis for the treatment of SCI.