Insecticide resistance in mosquitoes has become a severe impediment to global vector control and manifests as decreased insecticide effectiveness. The role of target site mutations and detoxification enzymes as resistance markers has been documented in mosquitoes; however, the emergence of complex resistant phenotypes suggest the occurrence of additional mechanisms. Cuticular proteins (CPs) are key constituents of the insect cuticle, and play critical roles in insect development and insecticide resistance. In this study, via electron microscopy we observed that the leg cuticle thickness in deltamethrin-resistant (DR) Anopheles sinensis mosquitoes was significantly greater than that measured in deltamethrin-susceptible (DS) An. sinensis. Transcription analysis revealed that cuticle proteins were enriched in the legs, including members of the CPR, CPAP, and CPF families. Further comparisons revealed the specific overexpression of four CP genes in the legs of DR An. sinensis; whose expression levels increased after treatment with deltamethrin. The RNAi-mediated silencing of one CP gene, AsCPF1, resulted in a significant decrease in the leg cuticle thickness of DR mosquitoes and significantly elevated the mortality rate when exposed to deltamethrin. These findings suggest that alterations in the An. sinensis leg cuticle contribute to the insecticide resistance phenotype. AsCPF1 is thereby a target study molecule for investigation of its mode of action, and broader attention should be paid to the role of mosquito legs in the development of insecticide resistance.