Neuroinflammation is being recognized as a hallmark of different neurodegenerative disorders including Alzheimer's disease. Suppressor of cytokine signaling 3 (SOCS3) is an anti-inflammatory molecule, which is known to inhibit cytokine signaling and inflammatory gene expression in different cells. However, the pathways by which SOCS3 could be upregulated in brain cells are poorly understood. Aspirin is a widely available pain reliever that is showing promise beyond its known pain-relieving capacity. This study underlines the importance of aspirin in upregulating SOCS3 in astrocytes and microglia. Aspirin increased the expression of Socs3 mRNA and protein in mouse astrocytes and BV-2 microglial cells in both a time- and dose-dependent manner. While investigating mechanism, we found that Socs3 gene promoter harbors PPRE and that aspirin upregulated SOCS3 in astrocytes isolated from PPARβ (-/-), but not PPARα (-/-), mice. Accordingly, aspirin increased SOCS3 in vivo in the cortex of wild type and PPARβ (-/-), but not PPARα (-/-), mice. Similarly, aspirin treatment increased astroglial and microglial SOCS3 in the cortex of FAD5X, but not FAD5X/PPARα (-/-), mice. Finally, recruitment of PPARα by aspirin to the proximal, but not distal, PPRE of the Socs3 promoter suggests that aspirin increases the transcription of Socs3 gene via PPARα. This study describes a novel property of aspirin in elevating SOCS3 in glial cells via PPARα and suggests that aspirin may be further considered for therapeutic application in neuroinflammatory and neurodegenerative disorders. This article is protected by copyright. All rights reserved.