Bombyx mori nucleopolyhedrovirus (BmNPV) is one of the most acute infectious diseases in silkworm, which has caused great economic loss in sericulture. Previous study showed that the content of components in mulberry leaves, particularly for moracin N, was increased after UV-B irradiation. In this study, the BmNPV resistance of silkworms reared on UV-B treated and moracin N spreaded mulberry leaves was improved. To uncover the mechanism of enhanced BmNPV resistance, silkworm midguts from UV-B treated mulberry leaves (BUM) and moracin N (BNM) groups were analyzed by SWATH-based proteomic technique. Of note, the abundance of ribosomal proteins in BUM and BNM groups was significantly changed to maintain the synthesis of total protein levels and cell survival. While, cytochrome c oxidase subunit II, calcium ATPase and programmed cell death 4 involved in apoptotic process were up-regulated in BNM group. Expressions of lipase-1, serine protease precursor, Rab1 protein, and histone genes were increased significantly in BNM group. These results suggest that moracin N might be the main active components in UV-B treated mulberry leaves to affect the BmNPV-resistance of silkworm, which could promote apoptotic cell death, enhance the organism immunity, and regulate the intercellular environment of cells in silkworm. It also presents an innovative process to reduce the mortality rate of silkworm infected with BmNPV.