The food and agriculture organization of the United Nations estimates that 20 - 40% of food yield is lost due to plant pests posing a severe food security threat. Sclerotinia stem rot (SSR; white mold) caused by Sclerotinia sclerotiorum, a broad host range fungal pathogen, was reported as the second most destructive soybean disease in the United States in the year 2021, leading to an estimated loss of nearly 25 million bushels of yield.  Understanding molecular plant resistance mechanisms to phytopathogens could deliver novel strategies to deploy resistant crop varieties. To unravel the molecular mechanisms governing resistance to S. sclerotiorum in soybean, we used multi-omics approaches, including dual RNA-seq, metabolomics, and chemical genomics. The study revealed that soybean resistance is associated in part with an earlier early accumulation of JA-Ile ((+)-7-iso-Jasmonoyl-L-isoleucine), a bioactive jasmonate, increased ability to scavenge ROS, and importantly a reprogramming of the phenylpropanoid pathway leading to increased antifungal activities. Indeed, we found that phenylpropanoid pathway intermediates such as cinnamic acid, 4-hydroxybenzoate, ferulic acid, and caffeic acid were highly accumulated in the resistant line compared to the susceptible line. In vitro assays showed that cinnamic acid, 4-hydroxybenzoate, ferulic, and caffeic acids affected S. Sclerotiorum growth and development. We further discuss and provide evidence for the importance of antifungal compounds during the resistance response against S. sclerotiorum. We show that this antifungal activity targets ergosterol biosynthesis in the fungus using chemical genomics as an important tool. This study provides an important step toward understanding the resistance responses of soybean to S. sclerotiorum and identifies novel mechanisms and targets to control sclerotinia stem rot to evolve durable resistance.