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Recent evidence have suggested that neuroinflammation and ischemia induce the activation of two different types of reactive astrocytes, termed A1 and A2. Additionally, A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative diseases, such as Alzheimer’s disease (AD). In the current study, we constructed an Aβ42‐activated microglia‐conditioned medium to induce A1 astrocytic activation via secretion of interleukin 1α, tumor necrosis factor, and complement component 1q in vitro, and indicated the regulatory role of milk fat globule epidermal growth factor 8 (MFG‐E8) on A1/A2 astrocytic alteration through the downregulation of nuclear factor‐κB and the upregulation of PI3K‐Akt. This study showed that MFG‐E8 suppressed A1 astrocytes and holds great potential for the treatment of AD.