Molecular signals mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. In this study, we demonstrate that peripheral lipopolysaccharide (LPS)-induced systemic inflammation could rapidly increase the plasma adenosine concentration, peaking at 6 hours post LPS injection (hpi). Using in vivo 2P-LSM imaging of adenosine sensor GRABAdo, we observed elevated adenosine levels in the cortex of awake mice, also peaking at 6 hpi. These concomitant pathological events strongly suggest adenosine in the circulation can join forces to the total central adenosine signal evoked by systemic inflammation. Combining immunohistochemistry, high-throughput RNA sequencing, cytokine array, and IMARIS analysis, we showed that increased adenosine triggered astrocytes at the early phase (2-6 hpi) of the systemic inflammation to promote astrocytic and microglial inflammatory responses. Deleting A1ARs in astrocytes prevented the upregulation of neuroinflammation-related proteins, BBB disruption, and aberrant neuronal functions upon peripheral LPS injection, which eventually ameliorated the systemic inflammation-induced depressive-like behaviour. In addition, A1ARs are Gi/o protein-coupled receptors. We expressed the chemogenetic tool hM4Di receptor in striatal A1AR-deficient astrocytes to induce the Gi signalling upon CNO administration, rescuing the phenotype of the astrocytic-A1AR deficient mice (e.g., restored depressive-like behaviour) in the peripheral LPS injection model. These observations suggest astrocytes rather than microglia as early drivers of neuroinflammation via A1ARs. In conclusion, the identification of peripheral and central levels of adenosine as pivotal signals offers novel drug targets for the treatment of SAE.