OBJECTIVE: The inflammatory response is integral to all stages of ischemic stroke. Unlike conventional reperfusion therapies, anti-inflammatory strategies offer a broader therapeutic window for treating ischemic stroke due to their capacity to attenuate inflammation. Astrocytes, once activated in ischemic conditions, significantly contribute to the production of inflammatory cytokines and exacerbate brain damage. While the neuroprotective effects of baicalin in post-stroke patients have been recognized, its role in modulating astrocyte activity and reducing inflammation remains under debate. This study aims to evaluate the impact of baicalin on astrocyte activation following ischemic stroke. METHODS: A model of ischemia/reperfusion (I/R) injury was induced in wild-type mice through transient middle cerebral artery occlusion (tMCAO). Mice were randomized into groups receiving either baicalin or saline. The expression levels of inflammatory markers-interleukin (IL)-6, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α)-were quantified using enzyme-linked immunosorbent assay (ELISA). Additionally, western blot analysis was employed to assess glial fibrillary acidic protein (GFAP) expression. RESULTS: Baicalin administration significantly mitigated neurological deficits in mice post-tMCAO. It reduced the activation of astrocytes and the production of pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and MCP-1, observed both in vivo and in vitro. In vitro studies also indicated a suppression of NF-κB activation. CONCLUSION: Baicalin effectively prevents ischemic brain damage by curtailing neuroinflammation and astrocyte activation. These findings advance the understanding of baicalin's mechanistic role in mitigating brain ischemia and support further investigation into its therapeutic potential.