Erythropoietin is a cytokine that binds to the Erythropoietin receptor and regulates the formation of erythroid cells during erythropoiesis in the bone marrow. However, many other organs and tissues express Erythropoietin and its receptor, such as the Nervous System, which principally regulates tissue protection. In the Central Nervous System, Erythropoietin is principally expressed by astrocytes, while neurons mainly express Erythropoietin receptors. Moreover, Erythropoietin acts as a pleiotropic molecule with neuroprotective effects, and its mechanisms of signal transduction pathways are defined, and there is a growing interest in its therapeutic potential. This review focuses on the role of Erythropoietin and its relationship with HIF1, PI3/Akt, GSK3B, JAK/STAT, and MAPKs signaling pathways that leads to cell survival after injury in the Central Nervous System. Knowledge of these signaling systems comprehensively could better guide EPO treatment to restoring different SNC alterations mediated by different insults.