Myocyte enhancer factor 2C (MEF2C) is highly expressed in the nervous system, and regulates neuro-development, synaptic plasticity, and inflammation. However, its mechanism in Alzheimer's disease (AD) is underestimated. In this study, the role and mechanism of MEF2C were investigated in the brain tissue specimens from patients with AD, APPswe/PSEN1dE9 double transgenic (APP/PS1_DT) mice, and SH-SY5Y cells treated with β-amyloid peptide (Aβ). The results indicated that the expression of MEF2C is significantly reduced, and the expression of MEF2C/Aβ in different parts of brain is negatively correlated in patients with AD. Knockdown of MEF2C promotes cell apoptosis and the level of β-amyloid precursor protein cleaving enzyme 1 (BACE) but reduces BACE2 expression. In addition, knockdown of enhances the generation and aggregation of Aβ in the cortex of APP/PS1_DT mice, reduces the expression of synaptic proteins, exacerbates the ability of learning and memory of APP/PS1_DT mice, damages the structure of mitochondria, increases the oxidative stress (OS) level, and inhibits the expression levels of members of the Nrf2-ARE signal pathway. In summary, inhibition of MEF2C exacerbates the toxic effect of Aβ and , damages synaptic plasticity, reduces the ability of learning and memory of APP/PS1 mice, and increases the level of OS via the Nrf2-ARE signal pathway.