This study investigates whether scutellarin promotes astrocyte polarization in MCAO and OGD models, and its effects on astrocyte-microglia, astrocyte-neuron interactions, and the PI3K-Akt pathway in neuroprotection. We used an experimentally induced cerebral ischemia rat model and OGD-stimulated TNC1 cell model. Using western blot, RT-qPCR and immunofluorescence, we show a noticeable increase in the expression of A2 astrocyte markers and a downregulation of A1 astrocyte markers in activated astrocytes, both in vivo and in vitro. Remarkably, after the treatment of scutellarin, OGD-stimulated TNC1 cells markedly downregulated M1 microglia markers and apoptosis factors in PC12 cells, while upregulating M2 microglia markers and anti-apoptosis factor Bcl2. Therefore, it is suggested that scutellarin can promote the polarization of activated astrocyte from the A1 to the A2 phenotype. Meanwhile, there is indeed a crosstalk between astrocytes-microglia and astrocytes-neurons, and astrocytes treated with scutellarin can promote M2 polarization of microglia and neuronal apoptosis. More importantly, based on the results of transcriptome sequencing, we used TNC1-pik3r1-siRNA cell model and pcDNA3.1 ( +)-pik3r1-TNC1 cell model to investigate the effect of the PI3K-Akt signaling pathway on the polarization of astrocyte and their crosstalk. Scutellarin promotes the A2 polarization, M2 polarization, and anti-apoptosis in astrocyte crosstalk by concomitantly enhancing the PI3K-Akt signaling pathway. This is strongly supported by observations in TNC1 astrocyte in TNC1-pik3r1-siRNA cell model, where the expression of A2 markers was decreased. Conversely, in the pcDNA3.1 ( +)-pik3r1-TNC1 cell model, expression was increased. In light of the above, the PI3K-Akt signaling pathway is considered a potential therapeutic target.