The orange wheat blossom midge (Sitodiplosis mosellana Géhin) is an insect pest that feeds on wheat (Triticum aestivum L.). The resistance mechanisms of wheat to S. mosellana infestation are largely unknown. In this study, the wheat varieties LX99 and 6218 were identified as highly resistant and susceptible, respectively, via field investigations conducted over 2 consecutive years. Morphological and microstructural observations of mature wheat kernels following S. mosellana infestation revealed that the degree of cell structure damage in resistant LX99 grains was less than that in susceptible 6,218 grains. Transcriptomic and metabolomic analyses of seeds following S. mosellana feeding showed that the differentially expressed genes and differentially accumulated metabolites from LX99 were mostly enriched in several primary and secondary metabolic pathways, including phenylpropanoid biosynthesis, flavonoid biosynthesis, and phenylalanine biosynthesis. Additionally, phenylpropanoid- and flavonoid-related gene expression was significantly upregulated following S. mosellana infestation in LX99 relative to that in 6218. Some metabolites involved in phenylpropanoid/flavonoid pathways, such as cinnamic acid, coumarin, epigallocatechin, and naringenin, were only induced in infested LX99 kernels. These results suggest that phenylpropanoid/flavonoid pathways play important roles in wheat kernel resistance to S. mosellana attack and provide useful insights for the breeding and utilization of resistant varieties.