Microglia-mediated neuroinflammation plays an important role in multiple sclerosis (MS). This study explored whether curcumin has a protective effect on experimental autoimmune encephalomyelitis (EAE), and the specific mechanism was investigated. We found that curcumin attenuates the severity of EAE mice. It inhibits the activation of microglia in the spinal cord of EAE mice and LPS-stimulated BV-2 cells. The findings clarify that curcumin may inhibit the inflammatory response mediated by microglia by inactivating the AXL/JAK2/STAT3 signaling pathway, which laid a theoretical foundation for the clinical management of MS.