The domesticated silkworm is an ideal and economic insect model that plays crucial roles in sericulture and bioreactor. Bombyx mori nucleopolyhedrovirus (BmNPV) is not only an infectious pathogen to B. mori, but also an efficient vector expressing recombinant proteins. Although, the proteomics of silkworm and BmN cell membrane lipid raft towards BmNPV infection had been investigated, proteome results of BmN cells upon BmNPV challenge currently remain ambiguous. In order to explore the interaction between silkworm and BmNPV, we analyzed several pivotal processes of BmNPV infected BmN cell by quantitative mass spectrometry. Our study indicated that a total of 4205 identified proteins, among which 4194 were with quantitative level. Concretely, during BmNPV infection, several transcription factors and epigenetically modified proteins showed substantially different abundance levels. Especially, proteins with binding activity, displayed significant changes in their molecular functions. Disabled non-homologous end joining by BmNPV reflects irreversible breakage of DNA. Nevertheless, highly abundant superoxide dismutase suggests that the cellular defense system is persistently functional in maintaining biochemical homeostasis. Our comparative and quantitative proteomics will be helpful to unravel the dynamics of B.mori after BmNPV infection and could provide new insights to decipher the mechanism of interaction between BmN cell and BmNPV.