NADPH–cytochrome P450 reductase (CPR) is the most important redox partner of various cytochrome P450 monooxygenases (P450s) and plays a central role in multiple metabolic reactions. In this paper, a full-length cDNA encoding CPR (designated as CmCPR) was characterized in the rice leaffolder, Cnaphalocrocis medinalis (Guenée), a serious lepidopteran rice pest. The complete open reading frame of CmCPR was 2046 bp, encoding a protein consists of 681 amino acid residues. The secondary structure of CmCPR protein showed marked features of classical CPRs such as N-terminal anchor, conserved functional domains, and catalytic residues. Phylogenic analysis showed that CmCPR was clustered together with CPRs from other lepidopteran species. Recombinant CmCPR protein was expressed in E. coli, and the activity and kinetic parameters of the enzyme were determined. Quantitative reverse transcription-PCR showed that the highest expression levels of CmCPR were detected in fourth- and fifth-instar larvae, and the transcriptional level in larval midgut tended to be higher than those in other tissues. Exposure to sublethal concentrations of three insecticides, abamectin, chlorpyrifos, and chlorantraniliprole, led to upregulated expression of CmCPR and several P450 genes. This work is the first report of molecular characterization of CPR gene in Cn. medinalis.