Neuroinflammation is a normal and healthy response to neuronal damage. However, excessive or chronic neuroinflammation exacerbates neurodegeneration after trauma and in progressive diseases such as Alzheimer’s, Parkinson’s, age-related macular degeneration, and glaucoma. Therefore, molecules that modulate neuroinflammation are candidates as neuroprotective agents. Erythropoietin (EPO) is a known neuroprotective agent that indirectly attenuates neuroinflammation, in part, by inhibiting neuronal apoptosis. In this review, we provide evidence that EPO also modulates neuroinflammation upstream of apoptosis by acting directly on glia. Further, the signaling induced by EPO may differ depending on cell type and context possibly as a result of activation of different receptors. While significant progress has been made in our understanding of EPO signaling, this review also identifies areas for future study in terms of the role of EPO in modulating neuroinflammation.