Although patients infected with the avian influenza H7N9 virus primarily present flu-like symptoms, recent clinical studies have found that viral encephalopathy caused by avian influenza H7N9 virus infection is an essential factor in patient deaths. In this study, the H7N9 virus was used to infect mouse microglia cells (MGs) BV2, central nervous system (CNS)-resident macrophages, to determine the infectivity of the H7N9 virus in MGs. Besides, we investigated immune reactions in H7N9 virus-infected mouse MGs by comprehensively analyzing the transcriptome and proteome. Results revealed that the H7N9 virus could infect BV2 cells, inducing cytopathic effects (CPEs) and producing infectious progeny virus. Furthermore, infection activated the tumor necrosis factor (TNF) signaling pathway and cleaved caspase-3, leading to cell death. These findings provide insights into the mechanisms by which the H7N9 virus causes lesions in the central nervous system.