Caterpillars limit soybean production, especially in the Southern USA, and thus require insecticide applications that increase production costs. However, as insecticides lose their effectiveness and climate change promotes caterpillar growth, caterpillars are an increasingly important pest in parts of the Midwest and into the Dakotas. Caterpillar pests are forecast to continue intensifying in the future. Nevertheless, genes for resistance to a broad range of caterpillars and other defoliators exist in soybean germplasm. We spent two decades making near isogenic lines with various combinations of these genes, enabling the study of resistance genes alone or in combination. We identified two QTLs that together are particularly effective. These were introgressed into new UGA elite lines, and the resulting lines are outstanding in the USDA preliminary soybean tests and the USDA uniform soybean tests, clearly showing the value of incorporating resistance to defoliating insects. One of the genes underlying a QTL has been cloned, and it is a non-functional flavonoid glucosyl transferase, with kaempferol as its most likely substrate. A candidate gene has been identified for the second QTL, and it is a transcription pathway that also helps regulate flavonoids. Non-targeted metabolomics identified 1064 metabolites that are upregulated in the resistant lines, but no new metabolites. Collectively, the results suggest that upregulated levels of flavonoids are responsible for resistance. Additional QTLs for defoliator resistance have been identified, and their study and evaluation should give additional insight into defoliator resistance in soybean.