The fall armyworm (FAW), Spodoptera frugiperda, is one of the major agricultural pests that has invaded China. The FAW is a polyphagous insect with the gramineous crop sorghum being a key host plant. However, the basis of sorghum's chemical defense against FAW feeding is still unclear. In this study, we investigated the potential defensive mechanism of sorghum against this insect species. It was found that FAW larvae preferred maize over sorghum, the selection and damage rates for sorghum plants by larvae were significantly lower than those of maize plants, and feeding on sorghum restricted larval weight. The non-target metabolomics revealed that the feeding of FAW larvae altered the plant secondary metabolite spectra in maize and sorghum, resulting in species-specific differential secondary metabolites (DSMs). Of these, 19 DSMs were specific in maize, and 51 in sorghum, and only 6 were found in both species. Two-choice and no-choice feeding assays found that gambogenic acid and chimonanthine, two DSMs unique to sorghum, were found to deter larval feeding and decrease the larval weight. These findings reveal that the defense of sorghum against FAW is regulated by changing the response spectra of secondary metabolites and that the induced metabolites have a defensive function by acting as antifeedants, which provides new insights into employing bioactive plant compounds against polyphagous insects.