Sclerotinia Stem Rot (SSR) caused by Sclerotinia sclerotiorum is one of the most devastating diseases on soybean and causes significant yield losses worlodwide. Current disease management strategies largely rely on fungicide applications. To develop additional tools to manage this disease, we considered targeting specific virulence factors in S. sclerotiorum using RNAi approaches. Oxalic acid is a known virulence factor for this fungus on soybean, and genes involved in its biosynthesis were identified. A gene (Ssoah1) encoding an oxaloacetate acetyl hydrolase is required for oxalic acid (OA) synthesis and was shown to be important for the pathogenic development of this fungus on soybean. Ssoah1-double-stranded/small interfering RNAs (dsRNA/siRNA) were synthesized and fluorescently labeled with Cy3 dye. Confocal imaging shows that S. sclerotiorum was able to uptake labeled ds/siRNAs, and this uptake resulted in decreased Ssoah1 transcript levels. Ssoah1-dsRNA/siRNA were also generated in planta using Virus-induced Gene Silencing (VIGS). Infections assays revealed that VIGS plants showed a decreased Ssoah1 gene expression and lower disease levels compared to empty vector control plants. Results of both assays indicate that Ssoah1-ds/siRNAs were successfully taken up by S. scleotiorum both in vitro and in planta, and conferred enhanced resistance to this pathogen. Our results suggest that HIGS is a viable control strategy against SSR in soybean.