Emerging evidence suggests that both selective and non-selective Adenosine A receptor (AR) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used animal model for multiple sclerosis (MS) research. Meanwhile, the recent FDA approval of Nourianz® (istradefylline) in 2019 as an add-on treatment to levodopa in Parkinson’s disease (PD) with “OFF” episodes, along with its proven clinical safety, has prompted us to explore the potential of AR antagonists in treating multiple sclerosis (MS) through clinical trials. However, despite promising findings in experimental autoimmune encephalomyelitis (EAE), the complex and contradictory role of AR signaling in EAE pathology has raised concerns about the feasibility of using AR antagonists as a therapeutic approach for MS. This review addresses the potential effect of AR antagonists on EAE/MS in both the peripheral immune system (PIS) and the central nervous system (CNS). In brief, AR antagonists had a moderate effect on the proliferation and inflammatory response, while exhibiting a potent anti-inflammatory effect in the CNS through their impact on microglia, astrocytes, and the endothelial cells/epithelium of the blood-brain barrier. Consequently, AR signaling remains an essential immunomodulator in EAE/MS, suggesting that AR antagonists hold promise as a drug class for treating MS.Copyright © 2023. Published by Elsevier Inc.