Cycloxaprid (CYC) is effective in the control of hemipteran pests, but its bioactivity against lepidopteran pests is still unclear. Here, the bioactivity of CYC against lepidopteran pests was found to be much worse than that against hemipteran insects. To reveal the mechanism, the transcriptomes of CYC-treated and untreated Ostrinia furnacalis larvae were compared. Among the top 20 differentially expressed genes, 11 encode proteins involved in cuticle formation, while only one encodes a detoxifying enzyme. Thus, the cuticle appears to be important for the insensitivity of O. furnacalis to CYC. A pretreatment of O. furnacalis larvae with methoprene enhanced the bioactivity of CYC by 1.12-fold. Moreover, mixtures of CYC with graphene oxide increased the bioactivity of CYC by 1.88-fold. Because lepidopteran and hemipteran insects often harm crops at the same time, the work can help make full use of CYC and reduce the environmental impacts of using multiple pesticides.