Salicylic acid (SA) is best known for orchestrating plant immune responses. SA signaling invokes the SA receptor NPR1 (Non-expresser of Pathogenesis-Related genes 1), which has an important role in plant defense against pathogens. SA contributes to resistance against Fusarium graminearum (Fg), which is the causal agent of Fusarium head blight (FHB) disease in wheat and barley, that can also infect leaf and floral tissues of Arabidopsis thaliana under laboratory conditions. NPR3 and NPR4 which are structurally related to NPR1, counteract the activation of NPR1-mediated defenses, by targeting NPR1 protein turnover and the suppression of transcription factors involved in defense gene expression. Knockdown of NPR3 and NPR4 results in enhanced resistance to some pathogens, confirming that they are susceptibility factors. To test whether similarly, NPR3 and NPR4 function as susceptibility factors for Fg infection in Arabidopsis and wheat, we tested the response of Arabidopsis and wheat plants containing mutations in the corresponding NPR3 and NPR4 genes for their response to Fg. We observed that the Arabidopsis npr3/npr4 mutants exhibited a hypersensitive-response (HR)-like phenotype that was accompanied by reduced fungal biomass accumulation and an increase in reactive oxygen species levels, expression of the SA-responsive defense gene PR1 and ion leakage. The inflorescence of npr3/npr4 mutant also exhibited enhanced resistance to Fg compared to wild-type plants. Similarly, missense mutations in wheat NPR3 (WhNPR3) and NPR4 (WhNPR4) promoted resistance to FHB, which was accompanied by reduced mycotoxin accumulation. The ability to knockdown NPR3 and NPR4 function to promote resistance to FHB in wheat holds promise for developing non-GMO approaches utilizing natural variants with missense and nonsense mutations that knockdown the activity of WhNPR3/WhNPR4. These natural variants could provide novel genetic material for integration into FHB resistance breeding programs.