Objective To explore the effect of different doses of hesperetin early intervention on β-amyloid transporter in APPswe/PS1dE9 transgenic mice. Methods The 3-month-old C57BL/6J wild type mice were set up as the control group, the 3-month-old APPswe/PS1d E9 transgenic mice were randomly divided into the model group, hesperetin low-dose group, medium-dose group and high-dose groups (20, 40, 80 mg·kg ^-1·d ^-1), and gavage once a day for 6 months. Immunohistochemistry was applied to test the expression of insulin-degrading enzyme (IDE) in brain tissue, Western blotting (WB) was applied to detect receptor of advanced glycation endproducts (RAGE), low density lipoprotein receptor-associated protein 1 (LRP-1) , P-glycoprotein (P-gp) and the blood-brain barrier related proteins Claudin-5, Occludin and occlusive zonolin-1 (ZO-1). Results Compared with the model group, IDE expression was significantly enhanced in three hesperetin groups. Compared with the control group, the model group exhibited decreased expressions of P-gp and LRP-1, increased expression of RAGE, and decreased expressions of Claudin-5, Occludin, and ZO-1. In contrast, compared with the model group, the hesperetin groups showed increased expressions of P-gp and LRP-1, decreased expression of RAGE, and increased expressions of Claudin-5, Occludin, and ZO-1(P<0.05). Conclusion Early intervention of hesperetin in APPswe/PS1dE9 mice can affect Aβ metabolismand transport by enhancing IDE activity, regulating Aβ transporter and blood-brain barrier tightness.