For a half-century, the commercial wild silkworm,Antheraea pernyi, has been protected by coumaphos, which is an internal organophosphorus insecticide used to kill the potential parasitic fly larvae inside. Knowledge about the detoxification genes ofA. pernyias well as the detoxification mechanism for this species remains severely limited. In this study, we identified 281 detoxification genes (32 GSTs, 48 ABCs, 104 CYPs, and 97 COEs) in the genome of this insect, which are unevenly distributed over 46 chromosomes. When compared to the domesticated silkworm,Bombyx mori, a lepidopteran model species,A. pernyihas a similar number of ABCs, but a greater number of GSTs, CYPs, and COEs. By transcriptome-based expression analysis, we found that coumaphos at a safe concentration level significantly changed the pathways related to ATPase complex function and the transporter complex inA. pernyi. KEGG functional enrichment analysis indicated that protein processing in the endoplasmic reticulum was the most affected pathway after coumaphos treatment. Finally, we identified four significantly up-regulated detoxification genes (ABCB1,ABCB3,ABCG11, andae43) and one significantly down-regulated detoxification gene (CYP6AE9) in response to coumaphos treatment, suggesting that these five genes may contribute to detoxification of coumaphos inA. pernyi. Our study provides the first set of detoxification genes for wild silkworms from Saturniidae and highlights the importance of detoxification gene repertoire in insect pesticide tolerance.