Objective To explore the effect of hesperetin early intervention to astrocyte in wild type and APPswe/PS1dE9 double transgenic mice. Methods The 3-month-old C57BL/6J wild type mice were set up as control group, hesperetin 10 mg/kg/d and 20 mg/kg/d group. The 3-month-old APPswe/PS1dE9 transgenic mice were set up as model group, hesperetin 20 mg/kg/d, 40 mg/kg/d, and 80 mg/kg/d groups, continuous intragastric administration for 6 months, once a day. The mice were killed after 6 months of intragastric administration, and 3-month-old C57BL/6J mice were purchased as normal control group. Immunohistochemical was used to test the expression of GFAP in mouse brain, double immunofluorescence staining was used to test the co-localized expressions of GFAP/C3 and GFAP/S100A10, Western Blot was used to observe the expression of GFAP and C3 in brain tissues of mice, IL-1α and TGF-β1 in brain tissue of mice were tested by using ELISA. Results Compared with the normal control group, the expression of GFAP and C3 in the control group increased, the number of GFAP/C3 colocalization positive cells increased, while the GFAP/S100A10 decreased. Compared with the control group, hesperetin could decrease the expression of GFAP, the number of GFAP/C3 colocation-positive cells, C3 as well as IL-1α, while the number of GFAP/S100A10 positive cells, TGF-β1 increased. Compared with the control group, the expression of GFAP, C3 in the model group increased, while the number of GFAP/S100A10 positive cells decreased. Compared with the model group, the expression of GFAP, C3 and the number of GFAP/C3 colocation-positive cells in hesperetin group decreased, while the expression of TGF-β1 and the number of GFAP/S100A10 colocation-positive cells increased (P<0.05). Conclusion Hesperetin early intervention can significantly alleviate the inflammation of naturally aged mice and transgenic mice, and its mechanism may be related to inhibiting the activation of astrocytes, promoting the activation of anti-inflammatory A2 cells, inhibiting the activation of pro-inflammatory A1 cells, and reducing the damage of neurons caused by inflammation.