Insects adapt to plant protease inhibitors (PIs) present in their diet by differentially regulating multiple digestive proteases. However, mechanisms regulating protease gene expression in insects are largely enigmatic. Ingestion of multi-domain recombinant protease inhibitor-7 (CanPI-7) arrests growth and development of (Lepidoptera: Noctuidae). Using RNA sequencing and proteomic analysis, we examined the response of larvae fed on recombinant CanPI-7 at different time intervals. Here, we present evidence supporting a dynamic transition in protease expression on CanPI-7 feeding with general down-regulation of protease genes at early time points (0.5 to 6 h) and significant up-regulation of specific trypsin, chymotrypsin and aminopeptidase genes at later time points (12 to 48 h). Further, coexpression of endogenous PIs with several digestive protease genes were apparent. In addition to the differential expression of endogenous PIs, we also observed a distinct novel isoform of endogenous PI in CanPI-7 fed larvae. Based on present and earlier studies, we propose potential mechanism of protease regulation in and subsequent adaptation strategy to cope with anti-nutritional components of plants.