Objective To investigate the effects of early intervention with different doses of hesperetin on learning and memory ability, amyloid beta protein 1-42(Aβ42) and neprilysin (NEP) activity in APPswe/PS1dE9 double transgenic mice. Methods Three month old C57BL/6J wild-type mice were used as control group(0.5% CMC-Na), and three month old APPswe/PS1dE9 double transgenic mice were used as model group, hesperetin low, medium and high dose groups (0, 20, 40 and 80 mg/kg/d), respectively. They were gavaged once a day for 6 months. Morris water maze behavior test was used to observe the learning and memory ability of mice; HE staining was used to observe the morphology of hippocampal neurons; ELISA was used to detect the content of Aβ 42 in serum; Western blot was used to detect the expression of Aβ 42 and neprilysin (NEP) in brain tissue. Results Compared with the control group, the incubation period of mice in the model group was significantly prolonged(P<0.05), the number of crossing platforms was reduced(P<0.05), the neurons in the hippocampal CA1 area were significantly damaged, the serum Aβ42 content was significantly increased(P<0.05), the content of Aβ42 in the brain tissue was significantly increased(P<0.01), and there was no significant difference in the content of NEP. Compared with the model group, the incubation period of mice in the low, medium and high dose groups of hesperetin was significantly shortened(P<0.01). The number of times increased(P<0.01), the morphological structure of hippocampal CA1 neurons was significantly improved, the content of Aβ42 in serum was significantly reduced(P<0.01), the content of Aβ42 in brain tissue was significantly reduced(P<0.01). The NEP content in the medium and high dose group were significantly increased(P<0.01). Conclusion Early intervention of hesperetin could significantly improve the learning and memory ability of APPswe/PS1dE9 double transgenic mice and neuronal damage in hippocampus CA1 area. The mechanism might be related to the increase of NEP activity and the enhancement of Aβ42 metabolism.