In spite of multiple studies elucidating individual defense mechanisms against stalk borer feeding, little information is available about the plant response to these members of Lepidoptera. Four maize inbred lines were cultivated in a greenhouse and challenged with larvae of the corn borer Sesamia nonagrioides. Transcriptome and biochemical analyses were performed to elucidate the maize response mechanisms to this insect. General plant defense mechanisms were activated, including the jasmonic acid biosynthetic pathway, proteinase inhibitors, and four defense-related transcription factors. Interestingly, gene ontology analysis shows that maize plants undergo cell-wall reorganization after being attacked. These results were confirmed through biochemical analyses showing that the concentration of some cell-wall-related compounds significantly changed after plant infestation in a genotype-dependent way. In conclusion, maize plants respond to the attack of the corn borer S. nonagrioides through cell-wall fortification, activating genes involved in cell-wall organization, which finally is reflected in a higher concentration of some cell-wall components, especially in resistant genotypes.