Cotton (Gossypium hirsutum) is an important fiber crop worldwide. Insect attack causes cotton yield and quality losses. However, little is known about the mechanism of cotton response to insect attack. We simulated insect feeding by applying insect oral secretions (OS) to wounds, and combined transcriptome and metabolome analysis to investigate how OS from two major pest species (Helicoverpa armigera and Spodoptera litura) affect cotton defense responses. We found that respectively 12,668 and 13,379 genes were differentially expressed in comparison with wounding alone. On addition of OS, the jasmonic acid signaling pathway was rapidly and strongly induced, whereas genes involved in salicylic acid biosynthesis were downregulated. On constructing a coexpression gene network, we identified a hub gene encoding a leucine-rich repeat receptor kinase that may play an important role in early signal recognition and transduction. OS from the two insect species altered the abundance of flavonoid-related compounds in different patterns. Gossypol remained in lower concentration after OS application than after wounding alone, suggesting a suppressive effect of OS on cotton defense response. This study illustrated transcriptional and metabolic changes of cotton in responding to OS from two chewing insect species, identified potential key response genes, and revealed evidence for OS inhibition of wounding-induced cotton defense response.