As widely used pesticides, organophosphate, pyrethroid, and neonicotinoid insecticides have different modes of action. In the present study, we evaluated individual and joint acute toxicities of two organophosphates, two pyrethroids, and two neonicotinoids against the second-instar silkworm by feeding silkworm with the insecticide-treated mulberry leaves. The 96-h lethal concentration 50 (LC₅₀) values of chlorpyrifos, acephate, imidacloprid, thiamethoxam, cypermethrin, and deltamethrin against silkworm were 3.45 (2.95–4.31), 44.45 (39.34–48.56), 1.27 (1.19–1.35), 2.38 (2.19–2.54), 0.36 (0.30–0.43), and 0.037 (0.033–0.041) mg/liter, respectively. Moreover, the 96-h LC₅₀ values of 50:50 binary mixtures of insecticides against silkworm ranged from 0.048 (0.043–0.054) to 3.52 (2.09–4.51) mg/liter. In addition, the combination coefficient (Q) values of all tested mixtures ranged from 0.36 to 3.37. According to the obtained Q values, the binary mixture of deltamethrin–chlorpyrifos showed antagonistic effects at 96-h interval, while the other binary mixtures had additive effects. Taken together, our results provided valuable guidelines in assessing the ecological risk of these insecticide mixtures against silkworm.