Erythropoietin (EPO) is a hormone that primarily regulates red blood cell production but also has neuroprotective effects. This study shows that EPO can cross the blood-brain barrier (BBB) and protect against brain injury. The EPO receptor (EPO-R) is abundantly expressed in brain capillaries, suggesting a pathway for EPO to enter the brain. Systemic administration of recombinant human EPO (r-Hu-EPO) before or up to 6 hours after focal brain ischemia reduced injury by 50–75%. r-Hu-EPO also ameliorates concussive brain injury, experimental autoimmune encephalomyelitis (EAE), and kainate-induced seizures. The study confirms that EPO can cross the BBB, as evidenced by biotinylated r-Hu-EPO being detected in brain sections. This suggests that EPO can act as a neuroprotective agent in various brain injuries. The study also shows that r-Hu-EPO is effective in reducing infarct volume in focal ischemic stroke models and in blunt trauma models. r-Hu-EPO reduces inflammation and protects against brain injury in EAE models. Additionally, r-Hu-EPO reduces the severity and latency of kainate-induced seizures. These findings suggest that r-Hu-EPO has broad neuroprotective effects and could be a potential treatment for various neurological conditions. The study highlights the importance of understanding how EPO crosses the BBB and its mechanisms of action in the brain. The results support the use of systemic r-Hu-EPO as a neuroprotective treatment in clinical settings.Erythropoietin (EPO) is a hormone that primarily regulates red blood cell production but also has neuroprotective effects. This study shows that EPO can cross the blood-brain barrier (BBB) and protect against brain injury. The EPO receptor (EPO-R) is abundantly expressed in brain capillaries, suggesting a pathway for EPO to enter the brain. Systemic administration of recombinant human EPO (r-Hu-EPO) before or up to 6 hours after focal brain ischemia reduced injury by 50–75%. r-Hu-EPO also ameliorates concussive brain injury, experimental autoimmune encephalomyelitis (EAE), and kainate-induced seizures. The study confirms that EPO can cross the BBB, as evidenced by biotinylated r-Hu-EPO being detected in brain sections. This suggests that EPO can act as a neuroprotective agent in various brain injuries. The study also shows that r-Hu-EPO is effective in reducing infarct volume in focal ischemic stroke models and in blunt trauma models. r-Hu-EPO reduces inflammation and protects against brain injury in EAE models. Additionally, r-Hu-EPO reduces the severity and latency of kainate-induced seizures. These findings suggest that r-Hu-EPO has broad neuroprotective effects and could be a potential treatment for various neurological conditions. The study highlights the importance of understanding how EPO crosses the BBB and its mechanisms of action in the brain. The results support the use of systemic r-Hu-EPO as a neuroprotective treatment in clinical settings.