Salicylic acid (SA) signaling mediated by Nonexpresser of Pathogenesis-Related Genes 1 (NPR1) is a key component of plant immune responses against pathogens such as Fusarium graminearum (hereafter abbreviated as Fg), the causal agent of Fusarium head blight (FHB) in wheat and barley. Under controlled laboratory conditions, Fg can also infect the leaves and flowers of Arabidopsis thaliana. The NPR1 homologs NPR3 and NPR4 have been identified as negative regulators of plant defense, as they promote NPR1 degradation and interfere with the activity of defense-related transcription factors. Considering the pivotal role of the SA–NPR1 pathway in both Arabidopsis and wheat resistance to Fg, we examined whether NPR3 and NPR4 contribute to plant susceptibility during interactions with Fusarium graminearum. Leaves of mutants lacking NPR3 or NPR4 in Arabidopsis showed defense-associated hypersensitive response (HR) phenotypes, including elevated reactive oxygen species accumulation, increased expression of the SA-responsive Pathogenesis-Related 1 (PR1) gene, enhanced ion leakage, and decreased fungal biomass. In addition, the inflorescences of these mutants were more resistant to Fg infection than those of wild-type plants. Likewise, missense mutations in wheat NPR3 and NPR4 genes, identified through a TILLING population, led to reduced FHB symptoms and lower levels of mycotoxin contamination. Altogether, these results indicate that NPR3 and NPR4 act as susceptibility factors in plant–Fg interactions and that downregulation of these genes offers an effective strategy to improve FHB resistance in wheat. The naturally occurring alleles of wheat NPR3 and NPR4, identified as part of this project, provide valuable non-GMO resources for developing FHB-resistant wheat varieties.