Objective To investigate the effect of β-asarone on differential protein expression in brain tissue of APPswe/PS1dE9 double transgenic mice, and to explore its mechanism in treatment of Alzheimer disease (AD). Methods The animals were divided into normal control group (C57BL/6J mice), model group (APPswe/PS1dE9 mice) and β-asarone treatment group (APPswe/PS1dE9 mice), with ten mice in each group. In a period of 90 days, the mice in β-asarone treatment group were administered with β-asarone by intragastric gavage (15 mg/[kg·d]), and the mice in normal control and model groups were administered with equal doses of normal saline. The learning and memory abilities of mice were detected by Morris water maze test. The expression of β-amyloid precursor protein (APP) in brain tissues was detected by immunohistochemistry. Proteomics analysis of brain tissues was performed by isobaric tags for relative and absolute quantification (iTRAQ). The expression of differential protein H2A and H2B was identified by Western blotting. Results Compared with the model group, the escape latency and the first latency time required to find the escaped platform of mice in the β-asarone treatment group were significantly shortened (P<0.05), the across-platform times were significantly increased (P<0.05), the expression of APP was significantly decreased (P<0.05), and the expressions of H2A 1-H, H2B 2-E and H2B 1-F/J/L were significantly decreased (P<0.05). Conclusion β-Asarone plays a therapeutic role by intervening the modification of histone, which might be one of the mechanisms to improve learning and memory abilities injured by the toxicity of β-amyloid peptide.